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Medicinal Properties of Cannabinoids, Terpenes, and Flavonoids in Cannabis, and Benefits in Migraine, Headache, and Pain: An Update on Current Evidence and Cannabis Science
Abstract
Background.—Comprehensive literature reviews of
historical perspectives and evidence supporting cannabis/
cannabinoids in the treatment of pain, including migraine
and headache, with associated neurobiological mechanisms
of pain modulation have been well described. Most of the
existing literature reports on the cannabinoids Δ9
-tetrahydrocannabinol (THC) and cannabidiol (CBD), or
cannabis in general. There are many cannabis strains that
vary widely in the composition of cannabinoids, terpenes,
flavonoids, and other compounds. These components work
synergistically to produce wide variations in benefits, side
effects, and strain characteristics. Knowledge of the individual
medicinal properties of the cannabinoids, terpenes, and
flavonoids is necessary to cross-breed strains to obtain
optimal standardized synergistic compositions. This will
enable targeting individual symptoms and/or diseases,
including migraine, headache, and pain.
Objective.—Review the medical literature for the use of
cannabis/cannabinoids in the treatment of migraine,
headache, facial pain, and other chronic pain syndromes, and
for supporting evidence of a potential role in combatting the
opioid epidemic. Review the medical literature involving
major and minor cannabinoids, primary and secondary
terpenes, and flavonoids that underlie the synergistic
entourage effects of cannabis. Summarize the individual
medicinal benefits of these substances, including analgesic
and anti-inflammatory properties.
Conclusion.—There is accumulating evidence for various
therapeutic benefits of cannabis/cannabinoids, especially in
the treatment of pain, which may also apply to the treatment
of migraine and headache. There is also supporting evidence
that cannabis may assist in opioid detoxification and weaning,
thus making it a potential weapon in battling the opioid
epidemic. Cannabis science is a rapidly evolving medical
sector and industry with increasingly regulated production
standards. Further research is anticipated to optimize
breeding of strain-specific synergistic ratios of cannabinoids,
terpenes, and other phytochemicals for predictable user
effects, characteristics, and improved symptom and diseasetargeted
therapies.
... THC is one of the phytocannabinoids present in the hemp seeds which have 20 times more anti-inflammatory property than aspirin and double as that of hydrocortisone. In addition to tetrahydrocannabinol, hemp seed also contains CBD which has similar properties like antiinflammatory and analgesic (Baron, 2018;EFSA, 2011;Fathordoobady et al., 2019). A large number of cannabidiol modulators containing amide are beneficial for the therapeutics of inflammation, rheumatoid arthritis, pain, allergies, nephritis, multiple sclerosis, glaucoma and brain tumours (Hanuš, 2009). ...
... It is also reported that when the diet is rich with hemp seed then it guards against neurodegenerative disease (Leonard et al., 2020). Tetrahydrocannabinol and other ingredients of hemp, in addition to other benefits, it is also found to be neuroprotective (Bapat, 2015;Baron, 2018). Some researchers have reported that when the rats were on diet with hemp seed, then they have shown noticeable longevity, the performance of memory was better and anti-ageing genes were also expressed. ...
... Hemp was used not only for the therapeutics of earache but also for reducing neurological discomfort (Lozano, 2001). The potency of hemp is highly appreciable for the therapeutics of chronic neuropathic pain which is partially assigned by the endocannabinoid system modification of the descending supraspinal inhibitory pathways where these pathways get frequently damage in chronic pain syndromes (Baron, 2018;Crescente et al., 2018). In addition to endocannabinoid, a large number of other groups have been used as neuroprotective agents (Hanuš, 2009). ...
Hemp seeds are gaining increasing attention in the realm of research due to their multifaceted nutritional and pharmaceutical properties. Notably, these seeds offer a rich source of protein, carbohydrates, polyunsaturated fatty acids, vitamins, and minerals, making them a valuable addition to one’s diet therefore, growing interest
among researchers globally. A comprehensive literature review was conducted on the prominent databases Scopus, Elsevier, and PubMed using the keywords "Hempseed," "Phytochemistry," "Nutraceuticals," and their food and feed applications. Studies suggest that these compounds exhibit therapeutic potential against conditions such as epilepsy, certain neurological disorders (Parkinson’s and Alzheimer’s diseases), and cardiovascular issues. Additionally, hemp seeds possess other notable properties, such as anti-cancer, anti-inflammatory, and immunomodulatory effects. They are also used as a dietary supplement to alleviate headaches, insomnia, high cholesterol levels, and premenstrual syndrome symptoms in women. Hempseed oil, powder, and flour are utilized to enhance the phenolic activity and antioxidant properties of food products. Additionally, hempseed cake, generated after cold pressing, boasts a high protein concentration, making it a valuable feed for ruminants. However, further research and clinical trials are necessary to fully understand and harness the potential of hemp seeds for functional foods and nutraceutical applications.
... For the treatment of headache, some plants have been mentioned that do not have the recognition of the EMA, but with evidence that validates this use: cannabis contains several cannabinoids, terpenes and flavonoids with anti-inflammatory, vasorelaxant and analgesic effects (Baron, 2018); Boswellia reduces the intensity and frequency of cluster headache (Lampl et al., 2012), and the topical use of peppermint essential oil in the treatment of tension headache has a similar efficacy to aspirin or acetaminophen (Göbel et al., 2016). Green tea and black tea were also mentioned. ...
... Para o tratamento da dor de cabeça foram referidas plantas sem o reconhecimento da EMA, mas com evidência que valida este uso: a cannabis contem diversos canabinóides, terpenos e flavonóides com efeitos anti-inflamatórios, vaso-relaxantes e analgésicos (Baron, 2018); a boswelia reduz a intensidade e frequência de cefaleia em salvas (Lampl et al., 2012), e o uso tópico do óleo essencial da hortelã-pimenta no tratamento da cefaleia de tensão tem uma eficácia semelhante à da aspirina ou do paracetamol (Göbel et al., 2016 ...
Introduction: Portugal has a long tradition of plants and herbal preparations for medicinal purposes (herbal medicines - HMs), but few studies on their use today. The professions of phytotherapy have recently been regulated, enabling more efficacy and safety. Objectives: 1) assess the use of HMs in Portugal, including attitudes, behaviors, sources of information, acquisition methods and role of HMs in health management, and identify the most used plants and targeted conditions. 2) evaluate them according to scientific evidence. Material and methods: a structured telephone interview. Scientific validity was assessed using the monographs of European Medicines Agency (EMA) and systematic reviews. Results: in this sample of 272 individuals, HMs are considered mainly for prevention or minor health problems. Family knowledge is the main information source and supermarkets/herb shops the main places of purchase, infusions being the preferred form. Two cases of mild adverse effects were reported. Most targeted conditions are flu, cold, cough, digestive discomfort and insomnia. The most used plants are: eucalyptus, elderberry, thyme, lemon, peppermint, echinacea, lemon balm, chamomile, valerian and passionflower. Conclusions: HM is mainly used for mild pathologies and chronic conditions. Its uses are mostly supported by scientific evidence. More attention to HMs from the medical community is important, in collaboration with phytotherapy and naturopathy professionals.
... In addition to cannabinoids, hemp is also a rich source of noncannabinoids phytochemicals like flavonoids (34), phenols (42), and terpenes (61 monoterpenes, 51 sesquiterpenes) [17]. These bioactive compounds can work both individually and synergistically interact with other bioactive phytochemicals, a phenomenon known as the entourage effect [3], to exert a variety of beneficial activities including anti-inflammatory, antimicrobial, and antioxidation [18,19]. These characteristics might play an important role in promoting the healthy husbandry of ruminants. ...
... Flavonoids and phenols are also important components of non-cannabinoid phytochemicals in hemp [17]. Cannabis has 26 distinct flavonoids, and the most important ones are apigenin, luteolin, quercetin, kaempferol, β-sitosterol, isovitexin, and orientin, as well as three flavonoids named cannflavin A, B, and C that are unique to cannabis [17,18]. However, most of the major flavonoids and phenols reported in cannabis were not detected in either the ruminal fluid or plasma of goat fed HF diet, which is likely due to the microbial degradation in the rumen. ...
Hemp forage (HF) seems a suitable forage for ruminants for its high nutritional value and rich phytochemicals that exert health and growth‐promoting activities. We investigated the effects of hemp‐related phytochemicals on rumen and plasma metabolism using metabolome when partially substituting alfalfa hay with HF in goat diets. Numbers of differential metabolites linearly increased with increasing HF substituting rate, approximately 50% of which were phytochemicals. Metabolic pathway enrichment analysis showed that the inclusion of HF greatly promoted steroid hormone biosynthesis, one carbon pool by folate, and retinol metabolism pathways in both rumen and plasma, which are beneficial for promoting animal health and well‐being and enhancing the quality of animal products. Some phytochemicals showed inhibitory activities on the growth of certain ruminal bacteria; meanwhile, the detected intermediate metabolites indicated degradation of the phytochemicals by ruminal microbes. These phytochemicals work individually and synergistically to alter ruminal and plasma metabolic pathways, thus exerting benefits in promoting the health and well‐being of animals.
... Thanks to all of them, CBD could help in conditions such as cardiovascular or neurological diseases, cancer and sclerosis, and alleviate the associated pain. Consequently, the companies have shown interest in this compound to produce a wide spectrum of products, from lotions to nutraceuticals (Baron, 2018;Pellati et al., 2018;White, 2019). ...
There is great interest in hemp cultivation to obtain an oil rich in cannabinoids. Cannabidiol (CBD) is the most sought after because it has remarkable medicinal properties. But hemp crops are sometimes improperly dried, leading to excessive bacteria and moulds growth during storage, which jeopardizes the microbiological quality of the oil. As a result, the crop must be discarded with a large economic impact. In this work, the microbial load of hemp and the obtained cannabinoid rich oil was assessed after extractions using supercritical CO2 and with three ethanol-based techniques (maceration, ultrasound, Soxhlet). Extremely high bioburden was found in the hemp, much of it sporulated forms that were difficult to inactivate. The microbial load of the exhausted hemp varied significantly depending on the extraction method, with ethanolic techniques achieving the highest reduction, while supercritical CO₂ ensured the complete elimination of fungi and enterobacteria. A clear relationship was found between higher hemp moisture and increased microbial inactivation during scCO2 extraction. Fortunately, all extraction techniques yielded sterile extracts. Further, the concentration of cannabinoids, chlorophylls and polyphenols, and the antioxidant capacity of the extracts were evaluated to determine if excessive moisture in the hemp negatively impacted the composition of the oil. On the contrary, the extracts were enriched in cannabinoids. Interestingly, the most concentrated oil (74 % total cannabinoids) was obtained from wet hemp by supercritical extraction. During this latter technique, part of the hemp moisture was removed, and the exhausted hemp was solvent-free, easing its future valorisation. Based on production costs, supercritical extraction was more profitable. Consequently, this work demonstrates that wet, highly biocontaminated hemp could still be a valuable raw material, and that supercritical extraction is the best technique to obtain a CBD oil of high quality from it.
... Em outro plano, a Cannabis sativa e os fitocanabinoides destacam-se após a descoberta dos receptores endocanabinoides e do papel desse sistema no corpo humano (Baron, 2018;Mouhamed et al., 2018) (Martins;Posso, 2023;Brasil, 2019). ...
A fibromialgia (FM) é um distúrbio neurossensorial caracterizado por dor musculoesquelética crônica, fadiga e distúrbios do sono. Seu tratamento é desafiador, e as terapias convencionais nem sempre são eficazes, impulsionando a busca por alternativas. Este estudo realizou uma meta-análise para comparar a eficácia dos canabinoides no controle da dor em FM em relação a outros tratamentos ou placebo. Foi conduzida uma revisão sistemática seguindo o modelo PRISMA, com busca em PUBMED/MEDLINE, BVS, Cochrane Database, Scopus e Web of Science. A análise de viés utilizou a ferramenta RoB 2.0, e a certeza das evidências foi avaliada pelo GRADE. Dos 94 estudos inicialmente identificados, apenas quatro ensaios clínicos randomizados, com 101 participantes, atenderam aos critérios de inclusão. A análise metodológica revelou viés significativo, principalmente na quebra de cegamento e na seleção dos desfechos. Além disso, os estudos apresentaram alta heterogeneidade entre si. Embora a terapia canabinoide seja considerada uma alternativa para FM, as evidências atuais são de baixa qualidade e não indicam significância estatística no alívio da dor para esses pacientes.
... Long-term studies have revealed various biological activities in all of the terpene's subgroups, including monoterpenes. However, the most important properties for human health are antioxidant/free radical scavenging, calming, antibacterial, and enzyme inhibition [1]. Natural compounds can be found in common plants used in everyday life or that surround us [2]. ...
Background/Objectives: Bicyclic monoterpenes are one of the most common groups of secondary plant metabolites found in Nature. Their wide spectrum of biological activity can be used in the prevention and in the treatment of various diseases, including so-called ‘diseases of civilization’. Their potential for synergistic interactions may influence the biological activities of more complex mixtures. Methods: This study investigated the ability of selected bicyclic monoterpenes and their binary mixtures to reduce Fe(III) and Cu(II) and chelate Fe(II) and assessed their cytotoxic activity against BJ and HepG2 cell lines. Results: The obtained results did not reveal synergistic interactions towards the biological activities, but binary mixtures proved to be safe in relation to the tested cell lines. Among the tested single monoterpenes, the most effective were 3-carene and β-pinene, with the latter exhibiting the greatest ability to decrease cell viability (CC50 for BJ and HepG2 cells was about 1.08 and 1.85 mM, respectively). Conclusions: The results revealed that both single compounds and binary mixtures demonstrate the ability to reduce selected metal ions and chelate Fe(II) ions. Synergistic interactions were not observed, but an increase in the activity of selected binary mixtures was recorded. Based on cell culture experiments, the monoterpenes and their binary mixtures can be considered safe at a concentration lower than 1 mM and close to 0.313 mM, respectively.
... has been suggested as a potential therapeutic option for managing coronavirus disease 2019 (Crippa et al., 2022). Cannabis was described in many literature for its therapeutic properties, including pain relief, anti-inflammatory effects, and its use in treating various ailments, such as rheumatism and malaria (Baron, 2018). Cannabis sativa plant contains over 550 natural components, with more than 120 of these being identified as "cannabinoids," which are unique to this plant (Rock and Parker, 2021;Wishart et al., 2024). ...
This study investigates the effects of early exposure to tetrahydrocannabinol (THC) and cannabidiol (CBD) on maternal and fetal development in Wistar rats. Female rats (90-120 g) were administered 150 mg/kg of cannabis extract (THC, CBD, or their combination) from gestational day 6 to day 19, with feed and water provided ad libitum. Cannabis extracts were prepared through ethanol extraction followed by rotary evaporation to isolate THC and CBD. The effects on body weight, placental morphology, and trophoblast cell count were assessed. Results showed that THC exposure during gestation significantly reduced fetal body weight on gestational day (GD) 19 and postnatal day (PND) 1, with the Early THC group showing a 27.7% reduction in weight at GD 19 and a 17.5% reduction at PND 1. CBD exposure resulted in a similar but less pronounced effect, with a 23.04% reduction in fetal weight at GD 19 and 18.2% at PND 1. The combination of THC and CBD resulted in a fetal weight reduction of 24.5% on GD 19 and 21.39%, falling between the reductions observed for THC and CBD alone. Placental weight and thickness were significantly altered in the THC and CBD groups, with a reduction in fetal-to-placenta weight ratio in all cannabis-exposed groups, indicating compromised placental efficiency. Histological analysis revealed significant reductions in cell counts in the labyrinth zone of the placenta, suggesting impaired trophoblast proliferation. These findings underscore the potential developmental disruptions caused by THC and CBD exposure, with significant effects on placental function and fetal growth. Further investigation is needed to understand the underlying mechanisms and long-term implications of cannabis exposure during pregnancy.
... The use of cannabis to alleviate pain in people has shown promise, however, a recent systematic review of the literature neither supported nor disproved the efficacy and safety of cannabis products for pain (51). With respect to migraine, several clinical trials have yielded promising results (52)(53)(54). Specifically, medicinal cannabis has been shown to reduce monthly migraine attacks and migraine severity with mild adverse effects (8,22). A recent clinical trial showed that vaporized cannabis flower containing 6% THC and 11% CBD was able to alleviate symptoms of pain, nausea, phonophobia, and photophobia in migraine patients (54). ...
Background
The therapeutic use of cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) to treat migraine has been understudied. Using three mouse models, we examined the impact of CBD and THC on migraine-relevant behaviors triggered by: 1) calcitonin gene-related peptide (CGRP), 2) sodium nitroprusside (SNP), and 3) cortical spreading depolarization (CSD).
Methods
Both male and female CD1 mice were treated with CBD (100 mg/kg) or THC (1 mg/kg) alone or in combinations of CBD (1, 30 or 100 mg/kg) and THC (1 mg/kg) prior to injection of CGRP or SNP. The mice were assessed for light aversion (photophobia), squint (non-evoked pain), and periorbital tactile hypersensitivity, as well as possible adverse effects. In a separate set of experiments, CSD events were optogenetically induced in familial hemiplegic migraine 1 (FHM1) mutant and wildtype littermates (WT) mice (C57BL/6 background), followed by grimace and motor assessments with and without combinations of CBD (30 or 100 mg/kg) and THC (1 mg/kg).
Results
In CD1 mice, a 100:1 CBD:THC combination mitigated light aversion induced by CGRP and SNP in males and females. Rescue of CGRP- and SNP-induced squint was observed only in male mice with 100:1 CBD:THC. None of the treatments rescued periorbital tactile hypersensitivity in either sex. In FHM1 mutant and WT mice, the 100:1 CBD:THC ratio did not affect CSD characteristics but did reduce CSD-induced grimace features (i.e., head pain mimic). No adverse effects of any of the cannabinoid treatments were observed using cognitive, emotional, or motor tests.
Conclusions
A 100:1 ratio of CBD:THC has a beneficial effect on some of the most bothersome migraine-related symptoms in three mouse models. Our findings support a potential therapeutic efficacy of combined CBD and THC treatments.
... Conversely, several universities in the West have conducted research programs that yielded conclusive results highlighting the medicinal significance of the chemical compounds produced by cannabis. The secondary metabolites of the cannabis plant, particularly cannabinoids, have shown promising potential in treating various diseases such as diabetes, pain, and depression [7,8]. Spe- In Nepal, a considerable portion of the economy is spent on purchasing expensive medicines from pharmaceutical companies around the world. ...
... Most cannabis products also contain cannabinoids other than THC that are of interest to researchers. For example, cannabidiol (CBD) is found in many cannabis products and is receiving growing research attention, in part owing to interest in its therapeutic potential [17][18][19][20], and to heterogeneity across clinical and preclinical evidence with respect to whether CBD attenuates or exacerbates the acute psychoactive effects of THC [21][22][23][24]. Further research is needed to clarify the acute effects of CBD, which requires survey methods for quantifying CBD use (akin to those emerging for quantifying THC use), the feasibility of which has yet to be established. ...
Aims
To establish the feasibility of using ecological momentary assessment (EMA) to estimate total quantities of Δ‐9‐tetrahydrocannabinol (THC) and cannabidiol (CBD) used across different forms of cannabis, and to assess the predictive validity of THC estimates for predicting acute cannabis‐related consequences.
Design
14‐day EMA using a smartphone application to assess cannabis use in real time.
Setting
Canada.
Participants
Targeted sample of n = 42 young adults (59.52% women, mean age 25 years) reporting frequent cannabis use.
Measurements
Surveys completed immediately prior to cannabis use assessed the quantities, THC content and CBD content of various forms of cannabis to be used in the current session; participants also uploaded photos of the cannabis product labels when available. Surveys administered at fixed times throughout the day (84.81% completion rate) assessed acute cannabis‐related consequences.
Findings
Participants completed a total of 786 pre‐cannabis surveys, of which 79.39% and 77.35% contained sufficient information to calculate total THC and CBD (in milligrams), respectively. High agreement was observed between participant‐entered THC and CBD contents and those shown in corresponding photos of cannabis product labels. Aggregating across all products used, participants reported using an average of 141.41 [standard deviation (SD) = 224.62, range = 0.00–2000.00] milligrams of THC (i.e. 28.28 standard five‐milligram units) and 7.53 (SD = 34.87, range = 0.00–484.22) milligrams of CBD per day. Multilevel models revealed that participants were more likely to report acute negative consequences following sessions when their estimated THC use was higher than their typical THC use. At the between‐person level, participants reporting more THC use on average across sessions were less likely to report negative consequences overall.
Conclusions
Using ecological momentary assessment to estimate total quantities of Δ‐9‐tetrahydrocannabinol and cannabidiol used across different forms of cannabis appears to be feasible, with preliminary predictive validity for acute negative cannabis‐related consequences.
... The effects of cannabinoids, terpenes, and flavonoids depend on their ratios, which can differ greatly between strains, leading to varying therapeutic results and side effects. [69][70][71] To mitigate these risks, it's important to standardize cannabis products to ensure consistent cannabinoid profiles and potency. 72 This includes ensuring consistent cannabinoid profiles and potency across batches. ...
The landscape of medical cannabis has evolved dramatically over the past few decades. Once stigmatized and illegal in most parts of the world, cannabis is now recognized for its potential therapeutic benefits, supported by an expanding body of scientific research. However, the transition from prohibition to medical recognition is shaped by complex interactions among scientific advancements, public perception and regulatory frameworks for its legalization. This review examines the recent breakthroughs in medical cannabis research, explores the shifting public perceptions and the stigma associated with its use and discusses strategies for enhancing the safety of medical cannabis. We also synthesize the connections between scientific research, public perception and safety considerations in the uses of medical cannabis, providing a comprehensive understanding of how these elements influence each other and shape the future of medical cannabis use for patient adherence.
... Besides cannabinoids, there are a lot of non-cannabinoid terpenes in the C. sativa raw material [134]. Generally, MC contains up to 200 different terpenoids [135]. The specific smell of C. sativa is due to its volatile mono-and sesquiterpenes such as β-myrcene and β-caryophyllene. ...
Chronic pain, lasting more than three months or persisting after normal healing, is a significant global health issue. As a healthcare system, it's crucial to ensure proper management of chronic pain. Traditional pharmacological and non-pharmacological pain management techniques may not fully meet the evidence requirements of doctors in terms of effectiveness and safety. Therefore, researchers are exploring natural analgesics. Plant-based phytoconstituents show promise in relieving chronic pain associated with various diseases.
This study aims to review the latest advances in discovering natural bioactive compounds that can help alleviate chronic pain. The article discusses the pathways of chronic pain and a multifactorial treatment strategy. It also organizes data on the use of plant-derived substances, such as cannabinoids, terpenoids, phenolics, and crude extracts. Additionally, it delves into the pharmacodynamics of cannabinoids, including their route of administration and elimination. The review presents the results of 22 clinical trials on various cannabinoids for pain relief. It's important to note that opioids and other alkaloids from plants are not covered in this article due to their primary use in controlling acute, rather than chronic, pain.
Keywords: herbal substances, crude extracts, cannabinoids, terpenoids, phenolic compounds, analgesic effect, pain sensation
... Cannabis products may also include additional cannabinoids, such as cannabinol (CBN) and cannabidiol (CBD), in addition to THC. The complexity of detection and quantification increases when many substances with different quantities and characteristics are present [24,25]. Smoking cannabis has severe effects on oral soft tissue, which results in 69.9% of users experiencing xerostomia, leucoedema, poor oral hygiene, periodontitis, and an increase in the density of candida albicans [26]. ...
The increasing use of illicit drugs has become a major global concern. Illicit drugs interact with the brain and the body altering an individual’s mood and behavior. As the substance-of-abuse (SOA) crisis continues to spread across the world, in order to reduce trafficking and unlawful activity, it is important to use point-of-care devices like biosensors. Currently, there are certain conventional detection methods, which include gas chromatography (GC), mass spectrometry (MS), surface ionization, surface-enhanced Raman spectroscopy (SERS), surface plasmon resonance (SPR), electrochemiluminescence (ECL), high-performance liquid chromatography (HPLC), etc., for the detection of abused drugs. These methods have the advantage of high accuracy and sensitivity but are generally laborious, expensive, and require trained operators, along with high sample requirements, and they are not suitable for on-site drug detection scenarios. As a result, there is an urgent need for point-of-care technologies for a variety of drugs that can replace conventional techniques, such as a biosensor, specifically an immunosensor. An immunosensor is an analytical device that integrates an antibody-based recognition element with a transducer to detect specific molecules (antigens). In an immunosensor, the highly selective antigen–antibody interaction is used to identify and quantify the target analyte. The binding event between the antibody and antigen is converted by the transducer into a measurable signal, such as electrical, optical, or electrochemical, which corresponds to the presence and concentration of the analyte in the sample. This paper provides a comprehensive overview of various illicit drugs, the conventional methods employed for their detection, and the advantages of immunosensors over conventional techniques. It highlights the critical need for on-site detection and explores emerging point-of-care testing methods. The paper also outlines future research goals in this field, emphasizing the potential of advanced technologies to enhance the accuracy, efficiency, and convenience of drug detection.
... 14,16,17 Cannabinoids may also dampen pain signaling by enhancing the activity of gamma amino butyric acid receptors in the spinal cord. 18 At the behavioral level, poor sleep quality is associated with worse pain outcomes such as lower pain threshold and increased pain reactivity. 19 The ECS seems to play a role in regulating the sleep-wake cycle possibly through the effect of endocannabinoids on rapid-eye movement sleep via the lateral hypothalamus. ...
Context/objective:
In-person hypnotic cognitive therapy (HYP-CT) is a promising treatment for chronic spinal cord injury-related pain. We describe the effects of HYP-CT delivered via Zoom (Z-HYP-CT) and compare the effects to historical controls who received hypnosis, cognitive therapy, or HYP-CT in-person.
Design:
Open pilot trial of HYP-CT versus historical controls.
Setting:
Telehealth study that recruited people with chronic SCI.
Participants:
Adults with moderate to severe chronic SCI-related pain.
Interventions:
Four weekly sessions of HYP-CT delivered via Zoom.
Outcome measures:
The primary outcome was average pain intensity on a 0-10 numerical rating scale measured at end of treatment (4 weeks) and 12 weeks. Secondary outcomes included pain interference, depression, sleep, pain catastrophizing, and pain self-efficacy.
Results:
23 individuals with SCI-related pain participated in the open trial and were compared to 21 historical controls. Average age was 54 years, 70% were male, and the majority were White. The participants were 11.6-13.1 years post-SCI and average pain intensity was 4.8-5.4/10. After Z-HYP-CT mixed-effects linear regressions showed that pain intensity was significantly less at 4 weeks (-1.28, P < .0001) and 12 weeks (-1.50, P < .0001) relative to baseline. Pain interference, depression, and pain catastrophizing also decreased significantly at both time points. There were no significant differences between the effects of Z-HYP-CT versus historical controls on any outcome variable.
Conclusion:
HYP-CT delivered via telehealth was associated with reduced pain intensity and other benefits that were comparable to the effect achieved by in-person historical controls. The effects of Z-HYP-CT should be evaluated using a randomized controlled design.
... Terpenes found in hemp are not unique to this plant, as they are also found in other plants. Many terpenes have medical potential, but their bioactivity obviously depends on the cannabis chemotype, due to terpenes and cannabinoids having different quantitative contents and ratios [10][11][12][13][14][15][16]. Of course, both the cannabis chemotype used and the patient's genetics play a major role in the treatment. ...
Terpenes and terpenoids content in cannabis plant was already studied in the past with three used methods. Since these works did not compare the content of these substances under the same conditions, we tried to make this comparison exactly. Three different gas chromatography/mass spectrometry (GS/MS) methods—hexane-based liquid extraction (Lis), static headspace extraction (HS), and headspace solid-phase microextraction (SPME)—were compared to identify volatile compounds in four different cannabis chemotypes—Green fields chemotype, Titan chemotype, Black Domina chemotype, and Neptune chemotype. The main compounds focused on were monoterpenes/monoterpenoids and sesquiterpenes/sesquiterpenoids. For a final evaluation of the comparison of the three methods of analysis, hexane extraction gives comparable results (which is advantageous for quantitative analysis), although the other two methods allowed the identification of more substances. This means that the same method should be used everywhere for the quantitative evaluation of constituents in cannabis.
... 1−7 Apart from the medicinal use of cannabis and the need for pharmaceutical-grade cultivars (i.e., genetic stability and reproducibility), there is a desire to influence cannabis offspring to produce unique secondary metabolite profiles. 8,9 Cannabis' vast genetic diversity enables a spectrum of aromas ranging from sweet, savory, or prototypical. 4,8,10−13 In particular, many cultivators aim to produce varieties that express unique aromatic and flavor characteristics that can significantly impact consumer preferences. ...
The recent increase in legality of Cannabis Sativa L. has led to interest in developing new varieties with unique aromatic or effect-driven traits. Selectively breeding plants for the genetic stability and consistency of their secondary metabolite profiles is one application of phenotyping. While this horticultural process is used extensively in the cannabis industry, few studies exist examining the chemical data that may differentiate phenotypes aromatically. To gain insight into the diversity of secondary metabolite profiles between progeny, we analyzed five ice water hash rosin extracts created from five different phenotypes of the same crossing using comprehensive 2-dimensional gas chromatography coupled to time-of-flight mass spectrometry, flame ionization detection, and sulfur chemiluminescence detection. These results were then correlated to results from a human sensory panel, which revealed specific low-concentration compounds that strongly influence sensory perception. We found aroma differences between certain phenotypes that are driven by key minor, nonterpenoid compounds, including the newly reported 3-mercaptohexyl hexanoate. We further report the identification of octanoic and decanoic acids, which are implicated in the production of cheese-like aromas in cannabis. These results establish that even genetically similar phenotypes can possess diverse and distinct aromas arising not from the dominant terpenes, but rather from key minor volatile compounds. Moreover, our study underscores the value of detailed chemical analyses in enhancing cannabis selective breeding practices, offering insights into the chemical basis of aroma and sensory differences.
... Nevertheless, there is still a fraction of our respondents using low-scientific-evidence CAMs, such as fasting, ketogenic diet, cannabis, oral therapies, reflexological massage and others. Beyond lacking evidence, some reports suggest these methods may even have a reverse, migraine triggering effects (8,(25)(26)(27)(28). ...
Object
This cross-sectional study aims to investigate migraineurs’ preferred complementary and alternative medicine (CAM) types and the factors influencing their usage.
Materials and methods
An anonymous e-survey was distributed to Lithuanian Migraine Association members, and social media migraine support communities. The collected data consisted of demographic, migraine-related questions, personal qualities, CAM habits.
Results
470 respondents were analyzed. 95.96% were women with a median age of 37 (IQR 31, 44). The median duration of migraine was 17.5 years (IQR 10, 25) and the median headache severity was rated 8 (IQR 7, 10) out of 10. 68.90% of participants had one or more headache days per week. 71.49% of respondents were triptan users, 27.66% used medical prophylaxis, and 17.87% used monoclonal antibodies. 52.55% of respondents used CAM in the past 12 months. Physical activity (36.17%), dietary changes/fasting (27.02%), relaxation/meditation (26.60%) were the most used CAM types. Reasons for CAM use included dissatisfaction with conventional treatment effectiveness (42.51%), concerns about safety (48.18%) and adverse effects (37.25%). Factors associated with the decision to explore CAM included longer headache duration (p = 0.017, Mann–Whitney U test), frequent sick leaves (p < 0.001, Mann–Whitney U test), current preventive medication use (p = 0.016, chi-square test), positive views on CAM safety/naturality (p = 0.001/ p < 0.001, Mann–Whitney U test), belief of having a healthy diet (p < 0.001, chi-square test), food-related worries (p = 0.011, Mann–Whitney U test) and Big-five personality trait of openness to experience (p = 0.049, chi-square test). After logistic regression, the frequent need to take sick leaves, having a healthy diet, food-associated fears maintained statistical significance. CAM use was not associated with non-adherence to conventional medicine. 48.99% of CAM consumers disclosed CAM use to their doctors.
Conclusion
CAM is explored by a significant proportion of migraineurs, less than half communicate this to their doctors. In our sample, physical activity, dietary changes, and relaxation techniques were the most common. Many patients opted for CAM due to previously experienced side effects/ineffectiveness of conventional migraine treatment or the fear of potential harm from standard medication. Individual factors, such as openness of personality can be an important contributing factor.
... Terpenes found in hemp are not unique to this plant, as they are also found in other plants. Many terpenes have medical potential but their bioactivity obviously depends on the cannabis chemotype, due to terpenes and cannabinoids having different quantitative contents and ratios [9][10][11][12][13][14][15]. Of course, both the cannabis chemotype used and the patient's genetics play a major role in the treatment. ...
Terpenes and terpenoids content in cannabis plant was already studied in the past with three used methods. Since these works did not compare the content of these substances under the same conditions, we tried to make this comparison exactly. Three different gas chromatography/mass spectrometry (GS/MS) methods - hexane based liquid extraction (Liq), static head-space extraction (HS), and head-space solid phase microextraction (SPME) – were compared to identify volatile compounds in four different cannabis chemotypes - Green fields, Titan chemotype, Black Domina chemotype, and Neptune chemotype. The main compounds focused on were monoterpenes/monoterpenoids and sesquiterpenes/sesquiterpenoids. Extraction with hexane gave comparable results, however the other two methods allowed for the identification of more substances. For the final evaluation of the comparison of the three methods of analysis, extraction with hexane gives comparable results (which is advantageous for quantitative analysis), although the other two methods allowed for the identification of more substances. This means that the same method should be used everywhere for the quantitative evaluation of constituents in cannabis.
... Su producto más valioso es una resina rica en terpenos y cannabinoides. Estos exhiben diversas propiedades psicoactivas y medicinales (Barón 2018), lo que ha generado un interés creciente en su producción comercial. En esta producción de cannabis con fines farmacéuticos, cuyas estrategias de manejo integrado de plagas restringen la aplicación de productos de síntesis química, la entomofauna presente se convierte en un componente fundamental del funcionamiento del sistema productivo (Taylor y Birkett 2020). ...
In the commercial production of medicinal cannabis, where the application of chemical synthesis products is restricted, the associated entomofauna is a fundamental component of the functioning of the productive system. Its characterization contributes to the generation of strategies aimed at improving production. Preserving these identified and cured specimens constitutes a natural historical archive of multiple uses. The objective of this work was to collect, determine and preserve arthropod specimens associated with the productive system of medicinal cannabis. The propagation, production, research and postharvest areas of a greenhouse crop were visited. The capture methods used were light traps, passages with an entomological net, an entomological vacuum cleaner, perimeter pitfall traps, and manual capture of specimens that were feeding on the plant tissues of the plants. The larval stages were reared to the adult stage to achieve their identification. 240 specimens belonging to 8 orders, 36 families and 73 species of insects were acquired. The highest percentage corresponded to the orders Coleoptera and Hymenoptera. In Coleoptera, species belonging to the families Melolonthidae, Carabidae and Silphidae, among others, were determined. Additionally, there were some families of Hymenoptera, Braconidae, Ichneumonidae and Formicidae. Species are reported according to their alimentary and/or functional roles as phytophagous, pollinators, detritivores, necrophagous, dung-eating, mycophagous, antiphagous, parasitoids, predators, and hyperparasitoids. Six groups of harmful insects for the crop were recognized: leafhoppers, mites, thrips, leaf and root aphids, mulch fly and defoliating lepidoptera. This work constitutes a significant advance in the investigation related to the entomofauna associated with the productive system of Cannabis sativa in Antioquia, Colombia.
... It is thought that the terpenes work together with cannabinoids to modify or enhance their effects. This is known as the 'entourage effect' (Baron, 2018). The cannabinoids and terpenes are produced in the plant's resin glands. ...
Cannabis is now one of the most thoroughly studied and analyzed plant materials. More than 100 cannabinoids have been isolated and identified in cannabis along with the primary psychoactive component, Δ9-tetrahydrocannabinol (Δ9-THC). In addition to Δ9-THC, there are other components of cannabis that are medically beneficial. For example, cannabidiol (CBD) and cannabigerol (CBG) can moderate or influence the psychoactive effects of Δ9-THC. The raw cannabis plant consists of cannabinoids in their acidic form. When someone states that cannabinoids are in their "acidic form", they are referring to the chemical structure of the compound itself. A cannabinoid in its acidic form has a carboxyl group (-COOH) attached. While tetrahydrocannabinolic acid (THCA) is the non-psychoactive precursor to THC, it does not bind to the CB1 and CB2 receptors. Instead, it binds with other cannabinoids receptors in the endocannabinoid system. When THC is not decarboxylated, it is THCA. Although THCA possesses therapeutic effects, like anti-inflammatory and neuroprotective qualities, it is not in its most beneficial or psychoactive form. Decarboxylation is a chemical reaction that removes a carboxyl group (-COOH) and releases carbon dioxide (CO2). The two main catalysts for decarboxylation to occur are heat and time. High CBD strains tend to decarboxylate a bit slower than those with high THC content. Decarboxylate high CBD strains by baking them for 15-20 minutes at 149°C and decarboxylate high THC strains by baking them for 10-18 minutes at the same temperature (149°C) in the oven. Full decarboxylation may require more time to occur. It is important to keep tight temperature control applying cannabis to various technological applications. While heat is needed to decarboxylate the acids into the active form of cannabinoids our bodies can use, extreme temperatures can destroy many of the important plant materials that contribute to positive health outcomes, like terpenes.
... 5 There is also an apparent positive shift in public perception regarding cannabis and cannabisbased products, which may be connected to the increase in research outputs highlighting the potential medicinal and therapeutic effects of cannabis and associated cannabinoids. [6][7][8] However, the lack of testing and standardized analytical methods for the quantification of CBD and other bioactive compounds in these goods poses challenges for quality control, regulatory compliance, and consumer safety. A number of products have reportedly been marketed as "THC free" but have been found to contain high levels of Δ9-THC. ...
... Renowned for its psychoactive properties and pain-relieving effects, THC plays a crucial role in managing conditions such as chronic pain and nausea [2]. On the other hand, CBD has gained attention for its potential anti-inflammatory, anticonvulsant, and anxiolytic properties, making it valuable in treating epilepsy, anxiety disorders, and inflammation-related conditions [3,4]. Although present in smaller quantities, CBG is recognized as a precursor to other cannabinoids and demonstrates neuroprotective and potential anti-inflammatory effects, making it an emerging target for research and medicinal applications [5,6]. ...
In the evolving field of cannabis research, scholars are exploring innovative methods to quantify cannabinoids rapidly and non-destructively. This study evaluates the effectiveness of a hand-held near-infrared (NIR) device for quantifying total cannabidiol (total CBD), total delta-9-tetrahydrocannabinol (total THC), and total cannabigerol (total CBG) in whole cannabis inflorescences. Employing pre-processing techniques, including standard normal variate (SNV) and Savitzky–Golay (SG) smoothing, we aim to optimize the portable NIR technology for rapid and non-destructive cannabinoid analysis. A partial least-squares regression (PLSR) model was utilized to predict cannabinoid concentration based on NIR spectra. The results indicated that SNV pre-processing exhibited superior performance in predicting total CBD concentration, yielding the lowest root mean square error of prediction (RMSEP) of 2.228 and the highest coefficient of determination for prediction (R²P) of 0.792. The ratio of performance to deviation (RPD) for total CBD was highest (2.195) with SNV. In contrast, raw data exhibited the least accurate predictions for total THC, with an R²P of 0.812, an RPD of 2.306, and an RMSEP of 1.651. Notably, total CBG prediction showed unique characteristics, with raw data yielding the highest R²P of 0.806. SNV pre-processing emerges as a robust method for precise total CBD quantification, offering valuable insights into the optimization of a hand-held NIR device for the rapid and non-destructive analysis of cannabinoid in whole inflorescence samples. These findings contribute to ongoing efforts in developing portable and efficient technologies for cannabinoid analysis, addressing the increasing demand for quick and accurate assessment methods in cannabis cultivation, pharmaceuticals, and regulatory compliance.
Background
Cannabidiol (CBD) is the primary non-psychoactive component of cannabis. Consumption of CBD is increasing rapidly as it is federally legal and widely available in the United States, Europe, Mexico, Canada, and Asia. CBD is gaining traction in medical and biochemical research, though a comprehensive classification of CBD receptor interactions is yet to be elucidated.
Methods
A comprehensive literature search across PubMed, Web of Science, and Google Scholar identified studies reporting cannabidiol (CBD) interactions with receptors, enzymes, and biological processes. Eligible articles included cell culture, animal model, biochemical, and clinical studies. Findings were thematically synthesized by body system, emphasizing mechanisms and implications for health and disease.
Results
Herein, I compile the literature to date of known interactions between CBD and various receptors, enzymes, and processes. I discuss the impact of CBD exposure on multiple processes, including endocannabinoid receptors, ion channels, cytochrome 450 enzymes, inflammatory pathways, and sex hormone regulation. I explain the potential effects of CBD on psychiatric disorders, seizure activity, nausea and vomiting, pain sensation, thermal regulation, neuronal signaling, neurodegenerative diseases, reproductive aging, drug metabolism, inflammation, sex hormone regulation, and energy homeostasis.
Conclusions
Understanding how CBD functions and how it can interact with other recreational or pharmaceutical medications is necessary for proper clinical management of patients who consume CBD.
Purpose of review
Cannabinoids have gained attention as a potential treatment for headache disorders, including migraine and cluster headache. While some studies suggest cannabinoids may provide analgesic and anti-inflammatory effects, concerns remain regarding their potential for overuse headache, cognitive impairment, and psychological dependence. This study critically evaluates the current evidence on cannabinoids in headache treatment, weighing their benefits and risks.
Recent findings
With the migraine treatment landscape expanding faster than ever, recent studies explore immune cells as a target for cannabinoids. Immune cells express cannabinoid and CGRP (calcitonin gene-related peptide) receptors. As a result, cannabinoids might potentially modulate the efficacy of current CGRP-targeting drugs. Additionally, emerging studies suggest that cannabinoids may enhance neuronal resilience and mitigate central sensitization in chronic migraine. Research into optimal delivery mechanisms, including inhaled, sublingual, and transdermal formulations, is also expanding.
Summary
Cannabinoids are being studied as a potential treatment for headache disorders, particularly migraine, due to their interaction with the endocannabinoid system, which regulates pain, inflammation, and vascular function. Studies suggest cannabinoids may help reduce headache frequency, alleviate pain, and improve sleep, though concerns remain about dependency, cognitive impairment, and medication overuse headache. While retrospective studies indicate benefits, the lack of standardized dosing, long-term safety data, and controlled trials limits conclusive recommendations. Comparisons with conventional treatments show mixed results, with cannabinoids presenting variable effectiveness and a risk of adverse effects. Further research, including randomized controlled trials, is needed to establish optimal dosing, safety, and efficacy in headache management.
Consumers can now purchase cannabinoid Cannabidiol (CBD) oil from retailers. Product names are often used to communicate the differences in the contents of CBD oils; for example, “CBD isolate” only contains CBD, whereas “full spectrum CBD” contains terpenes, flavonoids, and some delta‐9 tetrahydrocannabinol (THC). The names used to describe CBD oil could cause consumer confusion about actual product contents. We conducted an online survey with two product selection tasks to examine confusion associated with CBD oil names. Products in one selection task displayed names used to describe products, whereas the other selection task presented the attributes associated with the products. This design allowed us to conduct within‐subject tests to determine consumer confusion associated with the product names commonly used to describe CBD oils. This study provides valuable insights into consumer confusion and preferences regarding CBD products, and findings suggest that more detailed product attribute information can help reduce consumer confusion.
Chronic pain represents a complex and debilitating condition that affects millions of people worldwide, significantly compromising their quality of life. The conventional approach to treating this type of pain often relies on the use of opioid analgesics and anti-inflammatory drugs. While these agents are effective in the short term, they present several limitations, including the risk of dependence, severe side effects, and, in some cases, ineffectiveness in reducing pain. In this context, medical cannabis has emerged as a promising therapeutic alternative, given its potential ability to relieve pain effectively with a favorable safety profile. This work aims to provide a comprehensive and up-to-date review of the existing literature on the effects of medical cannabis in the treatment of chronic pain. Cannabis sativa contains several pharmacologically active compounds, the most prominent of which are delta-9-tetrahydrocannabinol (∆9-THC) and cannabidiol (CBD), which interact with the body’s endocannabinoid system, thereby modulating the pain response. Clinical evidence has shown that cannabinoids can significantly reduce the intensity of chronic pain, particularly in cases of neuropathy, multiple sclerosis, arthritis, and other painful conditions that are unresponsive to conventional treatments. However, the full integration of medical cannabis into clinical practice faces significant obstacles, including the need for standardized dosing, long-term safety data, and regulatory frameworks. These issues, alongside concerns over adverse effects and drug interactions, must be addressed to unlock the full therapeutic potential of cannabinoids, particularly for chronic pain patients, who endure both physical suffering and the added burden of stress.
Chronic pain lasting more than three months or persisting after normal healing is a significant global health issue. In a healthcare system, it is crucial to ensure proper chronic pain management. Traditional pharmacological and non-pharmacological pain management techniques may not fully meet the requirements of physicians regarding effectiveness and safety. Therefore, researchers are exploring natural analgesics. Plant-based phytoconstituents show promise in relieving chronic pain associated with various diseases. This study aims to review the latest advances in discovering natural bioactive compounds that can help alleviate chronic pain. It discusses the pathways of chronic pain and a multifactorial treatment strategy. It also organizes data on using plant- derived substances, such as cannabinoids, terpenoids, phenolics, and crude extracts. Additionally, it delves into the pharmacodynamics of cannabinoids, including their route of administration and elimination. The review presents the results of 22 clinical trials on various cannabinoids for pain relief. It is important to note that opioids and other alkaloids from plants are not covered in this article due to their primary use in controlling acute rather than chronic pain.
As terapias canabinóides estão ganhando força para o tratamento de diversas doenças, dentre elas, a migrânea. No entanto, ainda são necessários estudos para elucidar melhor o tratamento profilático e sintomático realizado com ela. Esta revisão de literatura tem o objetivo de analisar e sintetizar as evidências científicas disponíveis sobre a eficácia e segurança do Δ-9-tetraidrocanabinol (THC) como opção de tratamento profilático para a migrânea, visando identificar potenciais benefícios, mecanismos de ação, efeitos adversos e lacunas na literatura.
Recent research has uncovered that secondary metabolites-biologically active compounds produced by plants, microbes, and other organisms-play a significant role in regulating the differentiation and function of macrophages. Macrophages, key components of the innate immune system, are crucial for a wide range of physiological processes, including immune response modulation, tissue homeostasis, and host defense against pathogens. This research delves into the mechanisms by which secondary metabolites influence macrophage differentiation signaling pathways, with a focus on how specific compounds affect macrophage polarization and functional phenotypes. Understanding these effects can open new avenues for developing therapeutic strategies that target macrophage-mediated immune responses. Secondary metabolites, such as nitrogen (N) and sulfur (S) containing compounds, terpenoids, and phenolic compounds from plants and microbes, can modulate macrophage differentiation by influencing cytokine production and activity. The activation of signaling pathways in macrophages involves multiple receptors and transcription factors, including IFN-γ receptor activation leading to STAT1 activation, TLR4 triggering IRF5, NFκB, and AP1, IL-4 receptor activation leading to STAT6 and IRF4 activation, PPARγ activation via the fatty acid receptor, TLR4 increasing CREB and C/EBP levels. The complex interplay between transcription factors and cytokines is crucial for maintaining the balance between the M1 and M2 states of macrophages. Despite these insights, further research is needed to unravel the specific molecular mechanisms involved and to identify promising secondary metabolites that could be translated into clinical applications.
Registros históricos da Cannabis para fins medicinais são documentados há milhares de anos, sendo a Cannabis um Fitocanabinóide que assim como os Endocanabinóides podem se associar e ativar os receptores endógenos Canabinóides com afinidades variáveis, modulando funções regulatórias e interferindo nas vias de sinalização da dor. A exemplo da Dor de cabeça que tem como um dos mecanismos fisiopatológicos a estimulação excitatória no sistema trigeminovascular; e a ação de Cannabis nos receptores CB mostraram ter ação inibitória nestas vias, sinalizando uma diminuição dos efeitos da dor de cabeça. Assim, existe uma necessidade de investigação sobre possíveis mecanismos terapêuticos do uso da Cannabis para o tratamento da dor de cabeça. O seguinte trabalho consiste em uma revisão integrativa; e buscas foram realizadas nas plataformas SCIELO, PUBMED, SCOPUS e MEDLINE, utilizando-se as palavras chaves: “MEDICAL, CANNABIS” AND “TREATMENT” AND “HEADACHE”. Um total de 503 artigos foram encontrados, e destes após aplicados os critérios de inclusão e exclusão, apenas, 3 artigos foram selecionados para análise. Em conclusão os achados foram promissores quanto ao uso de Cannabis para o tratamento de dor de cabeça, sendo necessários maiores investigações.
Migraine is a prevalent neurovascular disorder with very few effective, known treatments. The role of Phytomedicine has been highlighted many times for the symptomatic treatment of various diseases and it stands true for migraine pain as well. The role of various herbal drugs such as Feverfew, Butterbur, Cannabis sativa, Saint John’s Wort, Damask Rose, Ginkgo biloba, Peppermint, Coriander, Chamomile, Petasites hybridus, Hypericum perforatum, Rosa damascena Mill., Mentha piperita, Coriandrum sativum, Matricaria chamomilla in the treatment of migraine pain has been highlighted in this chapter. The impact of various phytoconstituents present in these herbal drugs and the possible mechanisms such as anti-inflammation or neuroprotection by which they help provide symptomatic relief. Despite the fact that phytomedicine may prove to be an effective approach, there is need for more research and information regarding the efficacy, safety, and toxicity profile of these herbal drugs. Regardless of their side effects, phytomedicines hold tremendous potential and may be a comprehensive approach in migraine treatment.
Besides many other uses, dried Cannabis may be used for “tea” preparation. This study focused on a comprehensive characterization of an aqueous infusion prepared according to a common practice from three fairly different Cannabis cultivars. The transfer of 42 phytocannabinoids and 12 major bioactive compounds (flavonoids) into the infusion was investigated using UHPLC-HRMS/MS. Phytocannabinoid acids were transferred generally in a higher extent compared to their counterparts; in the case of Δ⁹-THC, it was only in the range of 0.4–1.9% of content in the Cannabis used. A dramatic increase of phytocannabinoids, mainly of the neutral species, occurred when cream was added during steeping, and the transfer of Δ⁹-THC into “tea” achieved a range of 53–64%. Under such conditions, drinking a 250 mL cup of such tea by a 70 kg person might lead to multiple exceedance of the Acute Reference Dose (ARfD), 1 μg/kg b.w., even in the case when using hemp with a Δ⁹-THC content below 1% in dry weight for preparation.
Cannabis‐infused foods are currently on the rise in markets all around the world. Meanwhile, there are concerns over the health implications for consumers. Studies have explored the therapeutic potential and nutritional and economic benefits of cannabis usage. Yet, the phytonutrients, processing methods, and health implications of cannabis‐infused foods have not been well explored. This review evaluates existing evidence on the nutritional, processing, safety, and phytonutrient composition of cannabis‐infused food products and their medicinal and functional prospects. Cannabis seeds contain the highest amount of dietary nutrients, while flowers contain the highest amount of bioactive constituents. Oils, butter, seeds, flowers, and leaf extracts are the plant forms currently incorporated into food products such as beverages, baked products, cooking ingredients, functional foods, nutraceuticals, and nootropics. Cannabis‐infused foods have been found to offer therapeutic benefits for pain management, brain function, gut health, and certain cancers. Findings also show significant constraints associated with cannabis‐infused foods regarding dosage guidelines, limited research, efficacy, and long‐term health effects on consumers. This is further worsened by the lack of policies that regulate the industry. To realize the full potential of cannabis use in the food and health industries and in research, regulatory guidelines are needed to control dosages and improve its efficient use in these industries. This will go a long way to ensure the safety of cannabis users and enhance responsible production, marketing, and distribution.
Zusammenfassung
Migräne ist nicht nur, aber auch eine Entzündungskrankheit. Substanzen, die antientzündlich wirken, müssten auch bei Migräne hilfreich sein. Migräne wird auch über den Serotoninstoffwechsel beeinflusst. Gelänge es uns, auf natürliche Weise den Serotoninspiegel anzuheben, sollte sich dies auch auf Migränefrequenz und -intensität auswirken. Nicht zuletzt können Omega-3-Fettsäuren zu einem Anstieg von Endocannabinoiden führen. Belege für diese physiologischen Grundlagen einer erfolgreichen Migräneprophylaxe werden im Beitrag ebenso aufgeführt wie klinische Studien zur Wirksamkeit sowie eine eindrucksvolle Kasuistik.
Cannabis use and cannabis use disorders have taken on a new social significance as a result of partial legalization. In 2021 a total of 4.5 million adults (8.8%) in Germany used the drug. The number of users as well as problematic use have risen in the last decade. Cannabis products with a high delta-9-tetrahydrocannabinol (THC) content and their regular use lead to changes in cannabinoid receptor distribution in the brain and to modifications in the structure and functionality of relevant neuronal networks. The consequences of cannabinoid use are particularly in the psychological functioning and can include intoxication, harmful use, dependence with withdrawal symptoms and cannabis-induced mental disorders. Changes in the diagnostics between ICD-10 and ICD-11 are presented. Interdisciplinary S3 guidelines on cannabis-related disorders are currently being developed and will be finalized shortly.
Scientific and public attention on the therapeutic effects of psychedelics and other psychoactive compounds in headache disorders has recently grown. The use and reported therapeutic effects of such treatments have long been reported, though formal clinical trials are only recently taking place. When considering how these substances might be further studied and eventually applied, it is important to consider the specific headache disorder, the particular drug, and the mode of use. No singular protocol will be applicable across all headache disorders and drugs. In this leading article, the nuance required to consider the value of classic psychedelics, ketamine, and cannabinoids as headache medicines is presented.
Studies with secretory cavity contents and air-dried inflorescence extracts of the CBD-rich hemp strain, Cannabis sativa cv. ‘Cherry Wine’, were conducted to compare the decarboxylation rates of acidic cannabinoids between two groups. The secretory cavity contents acquired from the capitate-stalked glandular trichomes by glass microcapillaries, and inflorescence samples air-dried for 15 days of storage in darkness at room temperature were analysed by high-pressure liquid chromatography. The ratio of acidic cannabinoids to the total cannabinoids was ranging from 0.5% to 2.4% lower in the air-dried inflorescence samples compared to the secretory cavity samples as follows. In the secretory cavity content, the percentage of acidic cannabinoids to the total cannabinoids was measured as 86.4% cannabidiolic acid (CBDA), 6.5% tetrahydrocannabinolic acid (THCA), 4.3% cannabichromenic acid (CBCA), 1.4% cannabigerolic acid (CBGA), and 0.6% cannabidivarinic acid (CBDVA), respectively. In the air-dried inflorescence, however, the acidic cannabinoids were detected with 84% CBDA, 4.8% THCA, 3.3% CBCA, 0.8% CBGA, and 0.3% Δ⁹-tetrahydrocannabivarinic acid (Δ⁹-THCVA), respectively. The ratio of cannabidiol (CBD) to cannabidiolic acid (CBDA) was close to 1:99 (w/w) in secretory cavity contents, however, it was roughly 1:20 (w/w) in the air-dried inflorescence. In addition, Δ⁹-tetrahydrocannabivarin (Δ⁹-THCV) and Δ⁹-tetrahydrocannabivarinic acid (Δ⁹-THCVA) were only detected in the air-dried inflorescence sample, and the ratio of Δ⁹-THCV to Δ⁹-THCVA was about 1:20 (w/w). Besides, cannabidivarinic acid (CBDVA) was only observed in the secretory cavity content.
A dor é uma experiência sensitiva e emocional desagradável associada, ou semelhante àquela associada, a uma lesão tecidual realou potencial. Quando persiste por mais de 90 dias, é considerada uma dor crônica (DC) ese torna uma doença. O efeito dos canabinoides na modulação da dorapresenta melhoriada qualidade de vida dos pacientes com DC, visto que o manejo dessa condição é comumente realizado poropioides, que podem levar à ocorrência de dependência,abstinência, tolerância e efeitos adversos. Nesse cenário, o presente estudo visa aenfatizaros benefícios da terapia com canabinoides no tratamento da DC, por meio de uma revisão narrativa. Como resultado, pode-se afirmar que os fitocanabinoidesse ligam aos receptores do sistema endocanabinoide e atuam como moduladores da dor por ação analgésica em estados inflamatórios e de hiperalgesia, minimizando respostas aos estímulos nocivos em aspecto comportamental e neurofisiológico. Visando a terapêutica das DCsrefratárias ao tratamento convencional,o uso dos canabinoides se apresenta como uma estratégia promissora, pois são capazes de atuar no alívio da dor e contribuir com a redução dos efeitos adversos associados ao uso de opioides conforme demonstrado em estudos.
Natural bioactives possess a wide range of chemical structures that can exert a plethora of pharmacological and toxicological actions, resulting in neuroprotection or neurotoxicity. These pharmacodynamic properties can positively or negatively impact human and animal global healthcare. Remarkably, Ayurvedic botanical Cannabis has been used worldwide by different ethnicities and religions for spiritual, commercial, recreational, nutraceutical, cosmeceutical, and medicinal purposes for centuries. Cannabis-based congeners have been approved by the United States of America's (USA) Food & Drug Administration (FDA) and other global law agencies for various therapeutic purposes. Surprisingly, the strict laws associated with possessing cannabis products have been mitigated in multiple states in the USA and across the globe for recreational use. This has consequently led to a radical escalation of exposure to cannabis-related substances of abuse. However, there is a lacuna in the literature on the acute and chronic effects of Cannabis and its congeners on various neuropathologies. Moreover, in the post-COVID era, there has been a drastic increase in the incidence and prevalence of numerous neuropathologies, leading to increased morbidity and mortality. There is an impending necessity for a safe, economically viable, multipotent, natural bioactive to prevent and treat various neuropathologies. The ayurvedic herb, Cannabis is one of the oldest botanicals known to humans and has been widely used. However, the comprehensive effect of Cannabis on various neuropathologies is not well established. Hence, this review presents effects of Cannabis on various neuropathologies.
In recent years, there have been significant growth and interest in cannabinoid-based drugs for a wide range of medical conditions, some of which are neurogenic diseases, pain control, and seizures. As there is an increased demand for cannabinoid-based drugs, it is necessary to adapt biotechnological techniques to develop new traits for the sophisticated and selective breeding of Cannabis plants aimed for cannabinoid production.
Despite Biotech companies aspiring to replace cannabis plants with heterologous hosts, genome editing for precision cannabis breeding is yet to be embraced. The availability of genome-editing technologies might herald a new dawn in breeding yielding new varieties with improved profiles of bioactive cannabinoids and terpenes. In this review, we highlight novel breeding approaches such as marker-assisted selection (MAS), mutation breeding, micropropagation, transgenic breeding, and CRISPR/Cas-based editing techniques aimed for enhanced cannabinoid production.
The individual and global burden of migraine is of such significance that there are accelerated efforts to develop new therapies. New migraine therapeutics are needed to address the current deficiencies that exist in the efficacy and adherence rate of approved anti-migraine medications. The recent discovery of the calcitonin gene related peptide as an add-on to the role of serotonin has markedly increased the range of new treatment options for acute and chronic migraine. Despite this, tackling the complexity of migraine disorders requires a complete understanding of its pathophysiology. Preclinical animal models can shed light on disease-related pathophysiology, including migraine. Indeed, the use of animal models has been instrumental in developing many therapeutics. However, an animal model is limited by the predictive and face validity of that model, and this extends to preclinical migraine models. In this review, a summary of the current understanding of the pathophysiology of migraine is given from both a preclinical and clinical perspective, and an emphasis is placed on the animal models of migraine. We will discuss the strengths and pitfalls of common preclinical migraine models as well as experimental research areas to explore further.
This study utilizes an all-payer database to compare 90-d and 1-year outcomes between marijuana and non-marijuana users undergoing total hip arthroplasty (THA). The primary aim of this study focused on 90-d and 1-year opioid consumption among marijuana users and non-users who underwent THA. Our secondary aim focused on comparing 90-d and 1-year rates of readmissions, revisions and adverse events between the two groups. A retrospective review was performed in the Mariner Database for all primary THA patients from 2010 to 2018. Marijuana users were identified utilizing International Classification of Diseases (ICD) 9 and 10 codes and matched 1:1 to non-marijuana users on age, sex, Charlson Comorbidity Index (CCI), obesity, alcohol, tobacco, illicit drug use, history of drug abuse, and presence of psychiatric history. This yielded a total of 1654 patients in each group. The 90-d and 1-year outcomes included opioid consumption, episode of care costs, readmissions, revisions, and complications. Chi-square was employed to assess categorical variables, while t -tests were employed for continuous variables. There was no difference in opioid consumption among marijuana users and non-marijuana users who underwent a THA. Marijuana use was associated with lower 90-d costs of care when compared with non-marijuana users. Marijuana users had higher rates of hip dislocation within 90 d and 1 year of surgery. Marijuana use is associated with higher 90-d and 1-year dislocation rates. THA recipients who use marijuana should be counseled concerning this increased risk. Prospective randomized control trials are needed to verify the results of this study.
We attempted to identify the antinociceptive and anti-inflammatory actions of the monoterpene p-cymene. Firstly, behavioural screening was carried out to verify the influence of p-cymene [25, 50, and 100 mg/kg intraperitoneal (i.p.)] on the central nervous system (CNS) activity. The antinociceptive activity of p-cymene was evaluated by the acetic acidinduced writhing response, formalin, and hot-plate test, respectively. The leukocyte migration induced by injection of carrageenan was used to assess the anti-inflammatory activity. p-Cymene showed depressant activity on CNS after 4 h of treatment and also a possible action on the autonomous nervous system (ANS), mainly at the dose of 100 mg/kg (i.p.). It was found that p-cymene (50 and 100 mg/kg, i.p.) significantly (p < 0.05) reduced the writhing responses induced by acetic acid. p-Cymene also decreased the licking time in the first and second phase, respectively, of the formalin test. The results of the hot-plate test showed that all doses of p-cymene increased significantly the latency time of the response to the thermal stimulus in both licking and jumping parameters. In addition, there was a significantly (p < 0.05) decreased leukocyte migration at all doses of p-cymene. The experimental data demonstrate that p-cymene possesses antinociceptive and anti-inflammatory activities
Background
Medicinal cannabis registries typically report pain as the most common reason for use. It would be clinically useful to identify patterns of cannabis treatment in migraine and headache, as compared to arthritis and chronic pain, and to analyze preferred cannabis strains, biochemical profiles, and prescription medication substitutions with cannabis.
Methods
Via electronic survey in medicinal cannabis patients with headache, arthritis, and chronic pain, demographics and patterns of cannabis use including methods, frequency, quantity, preferred strains, cannabinoid and terpene profiles, and prescription substitutions were recorded. Cannabis use for migraine among headache patients was assessed via the ID Migraine™ questionnaire, a validated screen used to predict the probability of migraine.
Results
Of 2032 patients, 21 illnesses were treated with cannabis. Pain syndromes accounted for 42.4% (n = 861) overall; chronic pain 29.4% (n = 598;), arthritis 9.3% (n = 188), and headache 3.7% (n = 75;). Across all 21 illnesses, headache was a symptom treated with cannabis in 24.9% (n = 505). These patients were given the ID Migraine™ questionnaire, with 68% (n = 343) giving 3 “Yes” responses, 20% (n = 102) giving 2 “Yes” responses (97% and 93% probability of migraine, respectively). Therefore, 88% (n = 445) of headache patients were treating probable migraine with cannabis. Hybrid strains were most preferred across all pain subtypes, with “OG Shark” the most preferred strain in the ID Migraine™ and headache groups. Many pain patients substituted prescription medications with cannabis (41.2–59.5%), most commonly opiates/opioids (40.5–72.8%). Prescription substitution in headache patients included opiates/opioids (43.4%), anti-depressant/anti-anxiety (39%), NSAIDs (21%), triptans (8.1%), anti-convulsants (7.7%), muscle relaxers (7%), ergots (0.4%).
Conclusions
Chronic pain was the most common reason for cannabis use, consistent with most registries. The majority of headache patients treating with cannabis were positive for migraine. Hybrid strains were preferred in ID Migraine™, headache, and most pain groups, with “OG Shark”, a high THC (Δ9-tetrahydrocannabinol)/THCA (tetrahydrocannabinolic acid), low CBD (cannabidiol)/CBDA (cannabidiolic acid), strain with predominant terpenes β-caryophyllene and β-myrcene, most preferred in the headache and ID Migraine™ groups. This could reflect the potent analgesic, anti-inflammatory, and anti-emetic properties of THC, with anti-inflammatory and analgesic properties of β-caryophyllene and β-myrcene. Opiates/opioids were most commonly substituted with cannabis. Prospective studies are needed, but results may provide early insight into optimizing crossbred cannabis strains, synergistic biochemical profiles, dosing, and patterns of use in the treatment of headache, migraine, and chronic pain syndromes.
-Tetrahydrocannabinol (THC) has complex effects on the cardiovascular system. We aimed to systematically review studies of THC and haemodynamic alterations. PubMed, Medline, and EMBASE were searched for relevant studies. Changes in blood pressure (BP), heart rate (HR), and blood flow (BF) were analysed using the Cochrane Review Manager Software. Thirty-one studies met the eligibility criteria. Fourteen publications assessed BP (number, n = 541), 22 HR (n = 567), and 3 BF (n = 45). Acute THC dosing reduced BP and HR in anaesthetised animals (BP, mean difference (MD) −19.7 mmHg, p < 0.00001; HR, MD −53.49 bpm, p < 0.00001), conscious animals (BP, MD −12.3 mmHg, p = 0.0007; HR, MD −30.05 bpm, p < 0.00001), and animal models of stress or hypertension (BP, MD −61.37 mmHg, p = 0.03) and increased cerebral BF in murine stroke models (MD 32.35%, p < 0.00001). Chronic dosing increased BF in large arteries in anaesthetised animals (MD 21.95 mL/min, p = 0.05) and reduced BP in models of stress or hypertension (MD −22.09 mmHg, p < 0.00001). In humans, acute administration increased HR (MD 8.16 bpm, p < 0.00001). THC acts differently according to species and experimental conditions, causing bradycardia, hypotension and increased BF in animals; and causing increased HR in humans. Data is limited, and further studies assessing THC-induced haemodynamic changes in humans should be considered.
Objective:
Research in both animals and humans indicates that cannabidiol (CBD) has antipsychotic properties. The authors assessed the safety and effectiveness of CBD in patients with schizophrenia.
Method:
In an exploratory double-blind parallel-group trial, patients with schizophrenia were randomized in a 1:1 ratio to receive CBD (1000 mg/day; N=43) or placebo (N=45) alongside their existing antipsychotic medication. Participants were assessed before and after treatment using the Positive and Negative Syndrome Scale (PANSS), the Brief Assessment of Cognition in Schizophrenia (BACS), the Global Assessment of Functioning scale (GAF), and the improvement and severity scales of the Clinical Global Impressions Scale (CGI-I and CGI-S).
Results:
After 6 weeks of treatment, compared with the placebo group, the CBD group had lower levels of positive psychotic symptoms (PANSS: treatment difference=-1.4, 95% CI=-2.5, -0.2) and were more likely to have been rated as improved (CGI-I: treatment difference=-0.5, 95% CI=-0.8, -0.1) and as not severely unwell (CGI-S: treatment difference=-0.3, 95% CI=-0.5, 0.0) by the treating clinician. Patients who received CBD also showed greater improvements that fell short of statistical significance in cognitive performance (BACS: treatment difference=1.31, 95% CI=-0.10, 2.72) and in overall functioning (GAF: treatment difference=3.0, 95% CI=-0.4, 6.4). CBD was well tolerated, and rates of adverse events were similar between the CBD and placebo groups.
Conclusions:
These findings suggest that CBD has beneficial effects in patients with schizophrenia. As CBD's effects do not appear to depend on dopamine receptor antagonism, this agent may represent a new class of treatment for the disorder.
Objectives:
To examine the association between Colorado's legalization of recreational cannabis use and opioid-related deaths.
Methods:
We used an interrupted time-series design (2000-2015) to compare changes in level and slope of monthly opioid-related deaths before and after Colorado stores began selling recreational cannabis. We also describe the percent change in opioid-related deaths by comparing the unadjusted model-smoothed number of deaths at the end of follow-up with the number of deaths just prior to legalization.
Results:
Colorado's legalization of recreational cannabis sales and use resulted in a 0.7 deaths per month (b = -0.68; 95% confidence interval = -1.34, -0.03) reduction in opioid-related deaths. This reduction represents a reversal of the upward trend in opioid-related deaths in Colorado.
Conclusions:
Legalization of cannabis in Colorado was associated with short-term reductions in opioid-related deaths. As additional data become available, research should replicate these analyses in other states with legal recreational cannabis.
Summary
Background
Comparable data on the global and country-specific burden of neurological disorders and their trends are crucial for health-care planning and resource allocation. The Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study provides such information but does not routinely aggregate results that are of interest to clinicians specialising in neurological conditions. In this systematic analysis, we quantified the global disease burden due to neurological disorders in 2015 and its relationship with country development level.
Methods
We estimated global and country-specific prevalence, mortality, disability-adjusted life-years (DALYs), years of life lost (YLLs), and years lived with disability (YLDs) for various neurological disorders that in the GBD classification have been previously spread across multiple disease groupings. The more inclusive grouping of neurological disorders included stroke, meningitis, encephalitis, tetanus, Alzheimer's disease and other dementias, Parkinson's disease, epilepsy, multiple sclerosis, motor neuron disease, migraine, tension-type headache, medication overuse headache, brain and nervous system cancers, and a residual category of other neurological disorders. We also analysed results based on the Socio-demographic Index (SDI), a compound measure of income per capita, education, and fertility, to identify patterns associated with development and how countries fare against expected outcomes relative to their level of development.
Findings
Neurological disorders ranked as the leading cause group of DALYs in 2015 (250·7 [95% uncertainty interval (UI) 229·1 to 274·7] million, comprising 10·2% of global DALYs) and the second-leading cause group of deaths (9·4 [9·1 to 9·7] million], comprising 16·8% of global deaths). The most prevalent neurological disorders were tension-type headache (1505·9 [UI 1337·3 to 1681·6 million cases]), migraine (958·8 [872·1 to 1055·6] million), medication overuse headache (58·5 [50·8 to 67·4 million]), and Alzheimer's disease and other dementias (46·0 [40·2 to 52·7 million]). Between 1990 and 2015, the number of deaths from neurological disorders increased by 36·7%, and the number of DALYs by 7·4%. These increases occurred despite decreases in age-standardised rates of death and DALYs of 26·1% and 29·7%, respectively; stroke and communicable neurological disorders were responsible for most of these decreases. Communicable neurological disorders were the largest cause of DALYs in countries with low SDI. Stroke rates were highest at middle levels of SDI and lowest at the highest SDI. Most of the changes in DALY rates of neurological disorders with development were driven by changes in YLLs.
Interpretation
Neurological disorders are an important cause of disability and death worldwide. Globally, the burden of neurological disorders has increased substantially over the past 25 years because of expanding population numbers and ageing, despite substantial decreases in mortality rates from stroke and communicable neurological disorders. The number of patients who will need care by clinicians with expertise in neurological conditions will continue to grow in coming decades. Policy makers and health-care providers should be aware of these trends to provide adequate services.
Funding
Bill & Melinda Gates Foundation.
Background
North America is currently in the grips of a crisis rooted in the use of licit and illicit opioid-based analgesics. Drug overdose is the leading cause of accidental death in Canada and the US, and the growing toll of opioid-related morbidity and mortality requires a diversity of novel therapeutic and harm reduction-based interventions. Research suggests that increasing adult access to both medical and recreational cannabis has significant positive impacts on public health and safety as a result of substitution effect. Observational and epidemiological studies have found that medical cannabis programs are associated with a reduction in the use of opioids and associated morbidity and mortality. Aims and Methods
This paper presents an evidence-based rationale for cannabis-based interventions in the opioid overdose crisis informed by research on substitution effect, proposing three important windows of opportunity for cannabis for therapeutic purposes (CTP) to play a role in reducing opioid use and interrupting the cycle towards opioid use disorder: 1) prior to opioid introduction in the treatment of chronic pain; 2) as an opioid reduction strategy for those patients already using opioids; and 3) as an adjunct therapy to methadone or suboxone treatment in order to increase treatment success rates. The commentary explores potential obstacles and limitations to these proposed interventions, and as well as strategies to monitor their impact on public health and safety. Conclusion
The growing body of research supporting the medical use of cannabis as an adjunct or substitute for opioids creates an evidence-based rationale for governments, health care providers, and academic researchers to consider the implementation and assessment of cannabis-based interventions in the opioid crisis.
Beneficial effects of cannabidiol (CBD) have been described for a wide range of psychiatric disorders, including anxiety, psychosis, and depression. The mechanisms responsible for these effects, however, are still poorly understood. Similar to clinical antidepressant or atypical antipsychotic drugs, recent findings clearly indicate that CBD, either acutely or repeatedly administered, induces plastic changes. For example, CBD attenuates the decrease in hippocampal neurogenesis and dendrite spines density induced by chronic stress and prevents microglia activation and the decrease in the number of parvalbumin-positive GABA neurons in a pharmacological model of schizophrenia. More recently, it was found that CBD modulates cell fate regulatory pathways such as autophagy and others critical pathways for neuronal survival in neurodegenerative experimental models, suggesting the potential benefit of CBD treatment for psychiatric/cognitive symptoms associated with neurodegeneration. These changes and their possible association with CBD beneficial effects in psychiatric disorders are reviewed here.
Various genetic factors can predispose individuals to migraines. For example, studies have shown that a decrease in expression of the cnr1 gene, which encodes the cannabinoid receptor type 1 (CB1) receptor, is associated with migraine and trigeminovascular activation.⁷⁰ Women who experience migraine also have increased activities of fatty acid amide hydrolase (FAAH), an enzyme used to degrade the endocannabinoid anandamide (AEA), and the endocannabinoid membrane transporter (EMT), a membrane transporter for AEA, leading to an overall decrease in levels of endocannabinoids.⁷³ This finding could partially explain the increased prevalence of migraines in women. An examination of cerebrospinal fluid shows that individuals who experience migraines have decreased levels of AEA and increased levels of CGRP and NO (normally inhibited by AEA). These findings support the proposed theory that alterations in endocannabinoid function with reductions in endocannabinoids such as AEA may be one of the mechanisms underlying migraine. A feature of headache disorders is that they are highly associated with other comorbidities, including anxiety and mood disorders, allergies, chronic pain disorders, and epilepsy.⁸⁶ The endocannabinoid deficiency hypothesis provides a possible mechanism underlying not only migraine but also diseases such as fibromyalgia and irritable bowel syndrome.⁷² Although the endocannabinoid deficiency hypothesis is still speculative and in need of further study, it suggests that exogenous stimulators of the endocannabinoid system, such as cannabis, could treat these diseases at their source.⁸⁷
Despite cannabidiol (CBD) having numerous cardiovascular effects in vitro, its haemodynamic effects in vivo are unclear. Nonetheless, the clinical use of CBD (Epidiolex) is becoming more widespread. The aim of this systematic review was to establish whether CBD is associated with changes in haemodynamics in vivo. Twenty-five studies that assessed the haemodynamic effects of CBD (from PubMed, Medline and EMBASE) were systematically reviewed and meta-analyzed. Data on blood pressure (BP), heart rate (HR), and blood flow (BF) were extracted and analyzed using random effects models. Twenty-two publications assessed BP and HR among 6 species (BP n = 344 and HR n = 395), and 5 publications assessed BF in 3 species (n = 56) after acute dosing of CBD. Chronic dosing was assessed in 4 publications in 3 species (total subjects BP, n = 6; HR, n = 27; BF, n = 3). Acute CBD dosing had no effect on BP or HR under control conditions. Similarly, chronic dosing with CBD had no effect on HR. In models of stress, acute CBD administration significantly reduced the increase in BP and HR induced by stress (BP, mean difference (MD) −3.54, 95% CI −5.19, −1.9, p < 0.0001; HR, MD −16.23, 95% CI −26.44, −6.02, p = 0.002). In mouse models of stroke, CBD significantly increased cerebral blood flow (CBF, standardized mean difference (SMD) 1.62, 95% CI 0.41, 2.83, p = 0.009). Heterogeneity among the studies was present, there was no publication bias except in HR of control and stressful conditions after acute CBD dosing, and median study quality was 5 out of 9 (ranging from 1 to 8). From the limited data available, we conclude that acute and chronic administration of CBD had no effect on BP or HR under control conditions, but reduces BP and HR in stressful conditions, and increases cerebral blood flow (CBF) in mouse models of stroke. Further studies are required to fully understand the potential haemodynamic effects of CBD in humans under normal and pathological conditions.
The endocannabinoid system plays a regulatory role in a number of physiological processes and has been found altered in different pathological conditions, including movement disorders. The interactions between cannabinoids and dopamine in the basal ganglia are remarkably complex and involve both the modulation of other neurotransmitters (γ-aminobutyric acid, glutamate, opioids, peptides) and the activation of different receptors subtypes (cannabinoid receptor type 1 and 2). In the last years, experimental studies contributed to enrich this scenario reporting interactions between cannabinoids and other receptor systems (transient receptor potential vanilloid type 1 cation channel, adenosine receptors, 5-hydroxytryptamine receptors). The improved knowledge, adding new interpretation on the biochemical interaction between cannabinoids and other signaling pathways, may contribute to develop new pharmacological strategies. A number of preclinical studies in different experimental Parkinson's disease (PD) models demonstrated that modulating the cannabinoid system may be useful to treat some motor symptoms. Despite new cannabinoid-based medicines have been proposed for motor and nonmotor symptoms of PD, so far, results from clinical studies are controversial and inconclusive. Further clinical studies involving larger samples of patients, appropriate molecular targets, and specific clinical outcome measures are needed to clarify the effectiveness of cannabinoid-based therapies.
Alzheimer's disease (AD) is a debilitating neurodegenerative disease that is affecting an increasing number of people. It is characterized by the accumulation of amyloid-β and tau hyperphosphorylation as well as neuroinflammation and oxidative stress. Current AD treatments do not stop or reverse the disease progression, highlighting the need for new, more effective therapeutics. Cannabidiol (CBD) is a non-psychoactive phytocannabinoid that has demonstrated neuroprotective, anti-inflammatory and antioxidant properties in vitro. Thus, it is investigated as a potential multifunctional treatment option for AD. Here, we summarize the current status quo of in vivo effects of CBD in established pharmacological and transgenic animal models for AD. The studies demonstrate the ability of CBD to reduce reactive gliosis and the neuroinflammatory response as well as to promote neurogenesis. Importantly, CBD also reverses and prevents the development of cognitive deficits in AD rodent models. Interestingly, combination therapies of CBD and Δ⁹-tetrahydrocannabinol (THC), the main active ingredient of cannabis sativa, show that CBD can antagonize the psychoactive effects associated with THC and possibly mediate greater therapeutic benefits than either phytocannabinoid alone. The studies provide “proof of principle” that CBD and possibly CBD-THC combinations are valid candidates for novel AD therapies. Further investigations should address the long-term potential of CBD and evaluate mechanisms involved in the therapeutic effects described.
Ethopharmacologic relevance:
Juniperus communis. L. is a shrub or small evergreen tree, native to Europe, South Asia, and North America, and belongs to family Cupressaceae. It has been used traditionally in unani system and in Swedish medicine as a decoction in inflammatory diseases. The main chemical constituents, which were reported in J. communis L. was α-pinene,, apigenin, sabinene, β-sitosterol, campesterol, limonene, Amentoflavone (AF), cupressuflavone, and many others.
Aim:
The aim of present study was to isolate the amentoflavone from the plant juniperus communis L. extracts and its protective effects against Freund's adjuvant induced arthritis in rats.
Material methods:
Adjuvant arthritis was induced by an injection of 1mg heat killed Mycobacterium tuberculosis (CFA) into the left hind paw of rat by sub planter route (at day 0). The experiment was designed and modified as per method available in literature.
Results:
The study showed that at a dose of 40mg/kg of amentoflavone (AF) from methanolic extract of Juniperus Communis L. possessed potentially useful anti-arthritic activity as it gave a positive result in controlling inflammation in the adjuvant induced experimental model.
Conclusion:
From the present experimental findings of both pharmacological and biochemical parameters observed, it had been concluded that at the doses of 20mg/kg and 40mg/kg of AF fraction from methanolic extract of Juniperus communis L. It possesses useful anti-arthritic activity since it gives a positive result in controlling inflammation in the adjuvant induced arthritic model in rats. The drug is a promising anti-arthritic agent of plant origin in the treatment of inflammatory disorders.
There is urgent need for the development of mechanistically different and less side-effect prone antipsychotic compounds. The endocannabinoid system has been suggested to represent a potential new target in this indication. While the chronic use of cannabis itself has been considered a risk factor contributing to the development of schizophrenia, triggered by the phytocannabinoid delta-9-tetrahydrocannabinol (Δ⁹-THC), cannabidiol, the second most important phytocannabinoid, appears to have no psychotomimetic potential. Although, results from animal studies are inconsistent to a certain extent and seem to depend on behavioral paradigms, treatment duration and experimental conditions applied, cannabidiol has shown antipsychotic properties in both rodents and rhesus monkeys. After some individual treatment attempts, the first randomized, double-blind controlled clinical trial demonstrated that in acute schizophrenia cannabidiol exerts antipsychotic properties comparable to the antipsychotic drug amisulpride while being accompanied by a superior, placebo-like side effect profile. As the clinical improvement by cannabidiol was significantly associated with elevated anandamide levels, it appears likely that its antipsychotic action is based on mechanisms associated with increased anandamide concentrations. Although, a plethora of mechanisms of action has been suggested, their potential relevance for the antipsychotic effects of cannabidiol still needs to be investigated. The clarification of these mechanisms as well as the establishment of cannabidiol’s antipsychotic efficacy and its hopefully benign side-effect profile remains the subject of a number of previously started clinical trials.
This article reviews recent research on cannabinoid analgesia via the endocannabinoid system and non-receptor mechanisms, as well as randomized clinical trials employing canna- binoids in pain treatment. Tetrahydrocannabinol (THC, Marinol ® ) and nabilone (Cesamet ® ) are currently approved in the United States and other countries, but not for pain indications. Other synthetic cannabinoids, such as ajulemic acid, are in development. Crude herbal cannabis remains illegal in most jurisdictions but is also under investigation. Sativex ® , a cannabis derived oromucosal spray containing equal proportions of THC (partial CB 1 receptor agonist ) and can- nabidiol (CBD, a non-euphoriant, anti-infl ammatory analgesic with CB 1 receptor antagonist and endocannabinoid modulating effects) was approved in Canada in 2005 for treatment of central neuropathic pain in multiple sclerosis, and in 2007 for intractable cancer pain. Numer- ous randomized clinical trials have demonstrated safety and effi cacy for Sativex in central and peripheral neuropathic pain, rheumatoid arthritis and cancer pain. An Investigational New Drug application to conduct advanced clinical trials for cancer pain was approved by the US FDA in January 2006. Cannabinoid analgesics have generally been well tolerated in clinical trials with acceptable adverse event profi les. Their adjunctive addition to the pharmacological armamentarium for treatment of pain shows great promise.
Anecdotal and scientific evidence suggests that Cannabis use may be beneficial in inflammatory bowel disease (IBD) patients. Here, we have investigated the effect of a standardized Cannabis sativa extract with high content of cannabidiol (CBD), here named CBD BDS for “CBD botanical drug substance,” on mucosal inflammation and hypermotility in mouse models of intestinal inflammation. Colitis was induced in mice by intracolonic administration of dinitrobenzenesulfonic acid (DNBS). Motility was evaluated in the experimental model of intestinal hypermotility induced by irritant croton oil. CBD BDS or pure CBD were given - either intraperitoneally or by oral gavage – after the inflammatory insult (curative protocol). The amounts of CBD in the colon, brain, and liver after the oral treatments were measured by high-performance liquid chromatography coupled to ion trap-time of flight mass spectrometry. CBD BDS, both when given intraperitoneally and by oral gavage, decreased the extent of the damage (as revealed by the decrease in the colon weight/length ratio and myeloperoxidase activity) in the DNBS model of colitis. It also reduced intestinal hypermotility (at doses lower than those required to affect transit in healthy mice) in the croton oil model of intestinal hypermotility. Under the same experimental conditions, pure CBD did not ameliorate colitis while it normalized croton oil-induced hypermotility when given intraperitoneally (in a dose-related fashion) or orally (only at one dose). In conclusion, CBD BDS, given after the inflammatory insult, attenuates injury and motility in intestinal models of inflammation. These findings sustain the rationale of combining CBD with other minor Cannabis constituents and support the clinical development of CBD BDS for IBD treatment.
A major factor associated with poor prognostic outcome after a first psychotic break is cannabis misuse, which is prevalent in schizophrenia and particularly common in individuals with recent-onset psychosis. Behavioral interventions aimed at reducing cannabis use have been unsuccessful in this population. Cannabidiol (CBD) is a phytocannabinoid found in cannabis, although at low concentrations in modern-day strains. CBD has a broad pharmacological profile, but contrary to ∆9-tetrahydrocannabinol (THC), CBD does not activate CB1 or CB2 receptors and has at most subtle subjective effects. Growing evidence indicates that CBD acts as an antipsychotic and anxiolytic, and several reports suggest neuroprotective effects. Moreover, CBD attenuates THC's detrimental effects, both acutely and chronically, including psychotogenic, anxiogenic, and deleterious cognitive effects. This suggests that CBD may improve the disease trajectory of individuals with early psychosis and comorbid cannabis misuse in particular-a population with currently poor prognostic outcome and no specialized effective intervention.
Objective:
We sought to quantify the anti-inflammatory effects of two cannabinoid drugs, cannabidiol (CBD) and palmitoylethanolamide (PEA), in cultured cell lines and compared this effect with experimentally inflamed explant human colonic tissue. These effects were explored in acutely and chronically inflamed colon, using inflammatory bowel disease and appendicitis explants.
Design:
Caco-2 cells and human colonic explants collected from elective bowel cancer, inflammatory bowel disease (IBD) or acute appendicitis resections, and were treated with the following drug treatments: vehicle, an inflammatory protocol of interferon γ (IFNγ) and tumour necrosis factor α (TNFα; 10 ng/ml), inflammation and PEA (10 µM), inflammation and CBD (10 µM), and PEA or CBD alone, CBD or vehicle were added simultaneously with IFNγ. Nine intracellular signalling phosphoproteins were determined by multiplex. Inflammatory cytokine secretion was determined using ELISA. Receptor mechanisms were investigated using antagonists for CB1, CB2, PPARα, PPARγ, TRPV1 and GPR55.
Results:
IFNγ and TNFα treatment increased phosphoprotein and cytokine levels in Caco-2 cultures and colonic explants. Phosphoprotein levels were significantly reduced by PEA or CBD in Caco-2 cultures and colonic explants. CBD and PEA prevented increases in cytokine production in explant colon, but not in Caco-2 cells. CBD effects were blocked by the CB2 antagonist AM630 and TRPV1 antagonist SB366791. PEA effects were blocked by the PPARα antagonist GW6471. PEA and CBD were anti-inflammatory in IBD and appendicitis explants.
Conclusion:
PEA and CBD are anti-inflammatory in the human colon. This effect is not seen in cultured epithelial cells. Appropriately sized clinical trials should assess their efficacy.
Pain is the most common manifestation of both acute and chronic inflammation that often challenges patients with rheumatic disease. Simply, we attribute this to local joint changes of pH in joints, the formation of radicals, enhanced joint pressure, or cytokine release acting on local nerves to produce pain. However, there is a more complex interplay of interactions between cytokines, mediators of inflammation, and ion channels that influence the final immune response and our perception of pain. Endocannabinoids, a group of less well-known endogenous bioactive lipids, have such manifold immunomodulatory effects able to influence both inflammation and pain. In this review, we overview the endocannabinoid system, its role in pain, inflammation, and immune regulation, and highlight the emerging challenges and therapeutic hopes.
The essential oil of black cumin seeds, Nigella sativa L., was tested for a possible antioxidant activity. A rapid evaluation for antioxidants, using two TLC screening methods, showed that thymoquinone and the components carvacrol, t-anethole and 4-terpineol demonstrated respectable radical scavenging property. These four constituents and the essential oil possessed variable antioxidant activity when tested in the diphenylpicrylhydracyl assay for non-specific hydrogen atom or electron donating activity. They were also effective ·OH radical scavenging agents in the assay for non-enzymatic lipid peroxidation in liposomes and the deoxyribose degradation assay.
Introduction: Epilepsy is one of the world’s oldest recognized and prevalent neurological diseases. It has a great negative impact on patients’ quality of life (QOL) as a consequence of treatment resistant seizures in about 30% of patients together with drugs’ side effects and comorbidities. Therefore, new drugs are needed and cannabinoids, above all cannabidiol, have recently gathered attention.
Areas Covered: This review summarizes the scientific data from human and animal studies on the major cannabinoids which have been of interest in the treatment of epilepsy, including drugs acting on the endocannabinoid system.
Expert commentary: Despite the fact that cannabis has been used for many purposes over 4 millennia, the development of drugs based on cannabinoids has been very slow. Only recently, research has focused on their potential effects and CBD is the first treatment of this group with clinical evidence of efficacy in children with Dravet syndrome; moreover, other studies are currently ongoing to confirm its effectiveness in patients with epilepsy. On the other hand, it will be of interest to understand whether drugs acting on the endocannabinoid system will be able to reach the market and prove their known preclinical efficacy also in patients with epilepsy.
A series of novel α-terpineol derivatives were designed and synthesized through structural derivatization of the tertiary hydroxyl moiety or reduction of the double bond. Of the resulting compounds, eight compounds enhanced relaxation of airway smooth muscle (ASM) compared to the α-terpineol precursor, and four compounds (4a, 4d, 4e, and 4i)were superior or comparable to aminophylline at a concentration of 0.75 mmol/L. Assays for 3′-5′-Cyclic adenosine monophpsphate (cAMP) activation revealed that some representative α-terpineol derivatives in this series were capable of upregulating the level of cAMP in ASM cells. Further in vivo investigation using the asthmatic rat model, illustrated that treatment with the compounds 4a and 4e resulted in significantly lowered lung resistance (RL) and enhanced dynamic lung compliance (Cldyn), two important parameters for lung fuction. Moreover, treatment with 4e downregulated the levels of both IL-4 and IL-17. Due to its several favorable physiological functions, including ASM relaxation activity, cAMP activation capability, and in vivo anti-asthmatic efficacy, 4e is a promising remedy for bronchial asthma, meriting extensive development.
Chronic pain states are highly prevalent and yet poorly controlled by currently available analgesics, representing an enormous clinical, societal, and economic burden. Existing pain medications have significant limitations and adverse effects including tolerance, dependence, gastrointestinal dysfunction, cognitive impairment, and a narrow therapeutic window, making the search for novel analgesics ever more important. In this article, we review the role of an important endogenous pain control system, the endocannabinoid (EC) system, in the sensory, emotional, and cognitive aspects of pain. Herein, we briefly cover the discovery of the EC system and its role in pain processing pathways, before concentrating on three areas of current major interest in EC pain research; 1. Pharmacological enhancement of endocannabinoid activity (via blockade of EC metabolism or allosteric modulation of CB1receptors); 2. The EC System and stress-induced modulation of pain; and 3. The EC system & medial prefrontal cortex (mPFC) dysfunction in pain states. Whilst we focus predominantly on the preclinical data, we also include extensive discussion of recent clinical failures of endocannabinoid-related therapies, the future potential of these approaches, and important directions for future research on the EC system and pain.
Background:
Cannabidiol (CBD) is a nonpsychoactive phytocannabinoid used in multiple sclerosis and intractable epilepsies. Preclinical studies show CBD has numerous cardiovascular benefits, including a reduced blood pressure (BP) response to stress. The aim of this study was to investigate if CBD reduces BP in humans.
Methods:
Nine healthy male volunteers were given 600 mg of CBD or placebo in a randomized, placebo-controlled, double-blind, crossover study. Cardiovascular parameters were monitored using a finometer and laser Doppler.
Results:
CBD reduced resting systolic BP (-6 mmHg; P < 0.05) and stroke volume (-8 ml; P < 0.05), with increased heart rate (HR) and maintained cardiac output. Subjects who had taken CBD had lower BP (-5 mmHg; P < 0.05, especially before and after stress), increased HR (+10 bpm; P < 0.01), decreased stroke volume (-13 ml; P < 0.01), and a blunted forearm skin blood flow response to isometric exercise. In response to cold stress, subjects who had taken CBD had blunted BP (-6 mmHg; P < 0.01) and increased HR (+7 bpm; P < 0.05), with lower total peripheral resistance.
Conclusions:
This data shows that acute administration of CBD reduces resting BP and the BP increase to stress in humans, associated with increased HR. These hemodynamic changes should be considered for people taking CBD. Further research is required to establish whether CBD has a role in the treatment of cardiovascular disorders.
The endocannabinoid system encompassing cannabinoid receptors, endogenous receptor ligands (endocannabinoids), as well as enzymes conferring the synthesis and degradation of endocannabinoids has emerged as a considerable target for pharmacotherapeutical approaches of numerous diseases. Besides palliative effects of cannabinoids used in cancer treatment, phytocannabinoids, synthetic agonists, as well as substances that increase endogenous endocannabinoid levels have gained interest as potential agents for systemic cancer treatment. Accordingly, cannabinoid compounds have been reported to inhibit tumor growth and spreading in numerous rodent models. The underlying mechanisms include induction of apoptosis, autophagy, and cell cycle arrest in tumor cells as well as inhibition of tumor cell invasion and angiogenic features of endothelial cells. In addition, cannabinoids have been shown to suppress epithelial-to-mesenchymal transition, to enhance tumor immune surveillance, and to support chemotherapeutics’ effects on drug-resistant cancer cells. However, unwanted side effects include psychoactivity and possibly pathogenic effects on liver health. Other cannabinoids such as the nonpsychoactive cannabidiol exert a comparatively good safety profile while exhibiting considerable anticancer properties. So far experience with anticarcinogenic effects of cannabinoids is confined to in vitro studies and animal models. Although a bench-to-bedside conversion remains to be established, the current knowledge suggests cannabinoid compounds to serve as a group of drugs that may offer significant advantages for patients suffering from cancer diseases. The present review summarizes the role of the endocannabinoid system and cannabinoid compounds in tumor progression.
Phytocannabinoids possess anticancer activity when used alone, and a number have also been shown to combine favourably with each other in vitro in leukaemia cells to generate improved activity. We have investigated the effect of pairing cannabinoids and assessed their anticancer activity in cell line models. Those most effective were then used with the common anti-leukaemia drugs cytarabine and vincristine, and the effects of this combination therapy on cell death studied in vitro. Results show a number of cannabinoids could be paired together to generate an effect superior to that achieved if the components were used individually. For example, in HL60 cells, the IC50 values at 48 h for cannabidiol (CBD) and tetrahydrocannabinol (THC) when used alone were 8 and 13 µM, respectively; however, if used together, it was 4 µM. Median-effect analysis confirmed the benefit of using cannabinoids in pairs, with calculated combination indices being <1 in a number of cases. The most efficacious cannabinoid-pairs subsequently synergised further when combined with the chemotherapy agents, and were also able to sensitise leukaemia cells to their cytotoxic effects. The sequence of administration of these drugs was important though; using cannabinoids after chemotherapy resulted in greater induction of apoptosis, whilst this was the opposite when the schedule of administration was reversed. Our results suggest that when certain cannabinoids are paired together, the resulting product can be combined synergistically with common anti-leukaemia drugs allowing the dose of the cytotoxic agents to be dramatically reduced yet still remain efficacious. Nevertheless, the sequence of drug administration is crucial to the success of these triple combinations and should be considered when planning such treatments.
Background
The Dravet syndrome is a complex childhood epilepsy disorder that is associated with drug-resistant seizures and a high mortality rate. We studied cannabidiol for the treatment of drug-resistant seizures in the Dravet syndrome.
Methods
In this double-blind, placebo-controlled trial, we randomly assigned 120 children and young adults with the Dravet syndrome and drug-resistant seizures to receive either cannabidiol oral solution at a dose of 20 mg per kilogram of body weight per day or placebo, in addition to standard antiepileptic treatment. The primary end point was the change in convulsive-seizure frequency over a 14-week treatment period, as compared with a 4-week baseline period.
Results
The median frequency of convulsive seizures per month decreased from 12.4 to 5.9 with cannabidiol, as compared with a decrease from 14.9 to 14.1 with placebo (adjusted median difference between the cannabidiol group and the placebo group in change in seizure frequency, −22.8 percentage points; 95% confidence interval [CI], −41.1 to −5.4; P=0.01). The percentage of patients who had at least a 50% reduction in convulsive-seizure frequency was 43% with cannabidiol and 27% with placebo (odds ratio, 2.00; 95% CI, 0.93 to 4.30; P=0.08). The patient’s overall condition improved by at least one category on the seven-category Caregiver Global Impression of Change scale in 62% of the cannabidiol group as compared with 34% of the placebo group (P=0.02). The frequency of total seizures of all types was significantly reduced with cannabidiol (P=0.03), but there was no significant reduction in nonconvulsive seizures. The percentage of patients who became seizure-free was 5% with cannabidiol and 0% with placebo (P=0.08). Adverse events that occurred more frequently in the cannabidiol group than in the placebo group included diarrhea, vomiting, fatigue, pyrexia, somnolence, and abnormal results on liver-function tests. There were more withdrawals from the trial in the cannabidiol group.
Conclusions
Among patients with the Dravet syndrome, cannabidiol resulted in a greater reduction in convulsive-seizure frequency than placebo and was associated with higher rates of adverse events. (Funded by GW Pharmaceuticals; ClinicalTrials.gov number, NCT02091375.)
The endocannabinoid (eCB) system has attracted attention for its role in various behavioral and brain functions, and as a therapeutic target in neuropsychiatric disease states, including anxiety disorders and other conditions resulting from dysfunctional responses to stress. In this mini-review, we highlight components of the eCB system that offer potential ‘druggable’ targets for new anxiolytic medications, emphasizing some of the less well-discussed options. We discuss how selectively amplifying eCBs recruitment by interfering with eCB-degradation, via fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), has been linked to reductions in anxiety-like behaviors in rodents and variation in human anxiety symptoms. We also discuss a non-canonical route to regulate eCB degradation that involves interfering with cyclooxygenase-2 (COX-2). Next, we discuss approaches to targeting eCB receptor-signaling in ways that do not involve the cannabinoid receptor subtype 1 (CB1R); by targeting the CB2R subtype and the transient receptor potential vanilloid type 1 (TRPV1). Finally, we review evidence that cannabidiol (CBD), while representing a less specific pharmacological approach, may be another way to modulate eCBs and interacting neurotransmitter systems to alleviate anxiety. Taken together, these various approaches provide a range of plausible paths to developing novel compounds that could prove useful for treating trauma-related and anxiety disorders.
Limonene, linalool and citral are common non-phenolic terpenoid components of essential oils, with attributed controversial antioxidant properties. The kinetics of their antioxidant activity was investigated using the inhibited autoxidation of a standard model substrate. Results indicate that antioxidant behavior of limonene, linalool and citral occurs by co-oxidation with the substrate, due to very fast self-termination and cross-termination of the oxidative chain. Rate constants kp and 2kt, (M⁻¹s⁻¹) at 30 °C were 4.5 and 3.5 × 10⁶ for limonene, 2.2 and 9.0 × 10⁵ for linalool and 39 and 1.0 × 10⁸ for citral. Behavior is bimodal antioxidant/pro-oxidant depending on the concentration. Calculations at the M05/6-311+g(2df,2p) level indicate that citral reacts selectively at the aldehyde C-H having activation enthalpy and energy respectively lower by 1.3 and 1.8 kcal/mol compared to the most activated allyl position. Their termination-enhancing antioxidant chemistry might be relevant in food preservation and could be exploited under appropriate settings.
Cannabinoids, when co-administered with opioids, may enable reduced opioid doses without loss of analgesic efficacy (ie an opioid-sparing effect). The aim of this study was to conduct a systematic review to determine the opioid-sparing potential of cannabinoids. Eligible studies included pre-clinical and clinical studies for which the outcome was either analgesia or opioid dose requirements. Clinical studies included controlled studies and case series. We searched Scopus, Cochrane Database of Systematic Reviews, Medline, and Embase. Nineteen pre-clinical and nine clinical studies met the search criteria. Seventeen of the 19 pre-clinical studies provided evidence of synergistic effects from opioid and cannabinoid co-administration. Our meta-analysis of pre-clinical studies indicated that the median effective dose (ED50) of morphine administered in combination with delta-9-tetrahydrocannabinol (delta-9-THC) is 3.6 times lower (95% CI 1.95, 6.76; n=6) than the ED50 of morphine alone. In addition, the ED50 for codeine administered in combination with delta-9-THC was 9.5 times lower (95% CI 1.6, 57.5, n=2) than the ED50 of codeine alone. One case series (n=3) provided very low-quality evidence of a reduction in opioid requirements with cannabinoid co-administration. Larger controlled clinical studies showed some clinical benefits of cannabinoids; however, opioid dose changes were rarely reported and mixed findings were observed for analgesia. In summary, pre-clinical studies provide robust evidence of the opioid-sparing effect of cannabinoids, while one of the nine clinical studies identified provided very low-quality evidence of such an effect. Prospective high-quality controlled clinical trials are required to determine the opioid-sparing effect of cannabinoids.
Over the past years, several lines of evidence support a therapeutic potential of Cannabis derivatives and in particular phytocannabinoids. Δ(9)-THC and cannabidiol (CBD) are the most abundant phytocannabinoids in Cannabis plants and therapeutic application for both compounds have been suggested. However, CBD is recently emerging as a therapeutic agent in numerous pathological conditions since devoid of the psychoactive side effects exhibited instead by Δ(9)-THC. In this review, we highlight the pharmacological activities of CBD, its cannabinoid receptor-dependent and -independent action, its biological effects focusing on immunomodulation, angiogenetic properties, and modulation of neuronal and cardiovascular function. Furthermore, the therapeutic potential of cannabidiol is also highlighted, in particular in nuerological diseases and cancer.
Background:
In 2014 Health Canada replaced the Marihuana for Medical Access Regulations (MMAR) with the Marihuana for Medical Purposes Regulations (MMPR). One of the primary changes in the new program has been to move from a single Licensed Producer (LP) of cannabis to multiple Licensed Producers. This is the first comprehensive survey of patients enrolled in the MMPR.
Methods:
Patients registered to purchase cannabis from Tilray, a federally authorized Licenced Producer (LP) within the MMPR, were invited to complete an online survey consisting of 107 questions on demographics, patterns of use, and cannabis substitution effect. The survey was completed by 271 respondents.
Results:
Cannabis is perceived to be an effective treatment for diverse conditions, with pain and mental health the most prominent. Findings include high self-reported use of cannabis as a substitute for prescription drugs (63%), particularly pharmaceutical opioids (30%), benzodiazepines (16%), and antidepressants (12%). Patients also reported substituting cannabis for alcohol (25%), cigarettes/tobacco (12%), and illicit drugs (3%). A significant percentage of patients (42%) reported accessing cannabis from illegal/unregulated sources in addition to access via LPs, and over half (55%) were charged to receive a medical recommendation to use cannabis, with nearly 25% paying $300 or more.
Conclusion:
The finding that patients report its use as a substitute for prescription drugs supports prior research on medical cannabis users; however, this study is the first to specify the classes of prescription drugs for which cannabis it is used as a substitute, and to match this substitution to specific diagnostic categories. The findings that some authorized patients purchase cannabis from unregulated sources and that a significant percentage of patients were charged for medical cannabis recommendations highlight ongoing policy challenges for this federal program.
The isolation and identification of the discrete plant cannabinoids in marijuana revived interest in analyzing historical therapeutic claims made for cannabis in clinical case studies and anecdotes. In particular, sources as old as the 11th and 15th centuries claimed efficacy for crude marijuana extracts in the treatment of convulsive disorders, prompting a particularly active area of preclinical research into the therapeutic potential of plant cannabinoids in epilepsy. Since that time, a large body of literature has accumulated describing the effects of several of the >100 individual plant cannabinoids in preclinical models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection. We surveyed the literature for relevant reports of such plant cannabinoid effects and critically reviewed their findings. We found that acute CB1R agonism in simple models of acute seizures in rodents typically produces anti-convulsant effects whereas CB1R antagonists exert converse effects in the same models. However, when the effects of such ligands are examined in more complex models of epilepsy, epileptogenesis and neuroprotection, a less simplistic narrative emerges. Here, the complex interactions between (i) brain regions involved in a given model, (ii) relative contributions of endocannabinoid signaling to modulation of synaptic transmission in such areas, (iii) multi-target effects, (iv) cannabinoid type 1 and type 2 receptor signaling interactions and, (v) timing, (vi) duration and (vii) localization of ligand administration suggest that there is both anti-epileptic therapeutic potential and a pro-epileptic risk in up- and down-regulation of endocannabinoid signaling in the central nervous system. Factors such receptor desensitization and specific pharmacology of ligands used (e.g. full vs partial agonists and neutral antagonists vs inverse agonists) also appear to play an important role in the effects reported. Furthermore, the effects of several plant cannabinoids, most notably cannabidiol (CBD) and cannabidavarin (CBDV), in models of seizures, epilepsy, epileptogenesis, and neuroprotection are less ambiguous, and consistent with reports of therapeutically beneficial effects of these compounds in clinical studies. However, continued paucity of firm information regarding the therapeutic molecular mechanism of CBD/CBDV highlights the continued need for research in this area in order to identify as yet under-exploited targets for drug development and raise our understanding of treatment-resistant epilepsies. The recent reporting of positive results for cannabidiol treatment in two Phase III clinical trials in treatment-resistant epilepsies provides pivotal evidence of clinical efficacy for one plant cannabinoid in epilepsy. Moreover, risks and/or benefits associated with the use of unlicensed Δ(9)-THC containing marijuana extracts in pediatric epilepsies remain poorly understood. Therefore, in light of these paradigm-changing clinical events, the present review's findings aim to drive future drug development for newly-identified targets and indications, identify important limitations of animal models in the investigation of plant cannabinoid effects in the epilepsies, and focuses future research in this area on specific, unanswered questions regarding the complexities of endocannabinoid signaling in epilepsy. This article is part of a Special Issue titled Cannabinoids and Epilepsy.
Treatment-resistant epilepsy (TRE) affects 30% of epilepsy patients and is associated with severe morbidity and increased mortality. Cannabis-based therapies have been used to treat epilepsy for millennia, but only in the last few years have we begun to collect data from adequately powered placebo-controlled, randomized trials (RCTs) with cannabidiol (CBD), a cannabis derivative. Previously, information was limited to case reports, small series, and surveys reporting on the use of CBD and diverse medical marijuana (MMJ) preparations containing: tetrahydrocannabinol (THC), CBD, and many other cannabinoids in differing combinations. These RCTs have studied the safety and explored the potential efficacy of CBD use in children with Dravet Syndrome (DS) and Lennox-Gastaut Syndrome (LGS).
The role of the placebo response is of paramount importance in studying medical cannabis products given the intense social and traditional media attention, as well as the strong beliefs held by many parents and patients that a natural product is safer and more effective than FDA-approved pharmaceutical agents. We lack valid data on the safety, efficacy, and dosing of artisanal preparations available from dispensaries in the 25 states and District of Columbia with MMJ programs and online sources of CBD and other cannabinoids. On the other hand, open-label studies with 100 mg/ml CBD (Epidiolex®, GW Pharmaceuticals) have provided additional evidence of its efficacy along with an adequate safety profile (including certain drug interactions) in children and young adults with a spectrum of TREs. Further, Phase 3 RCTs with Epidiolex support efficacy and adequate safety profiles for children with DS and LGS at doses of 10- and 20-mg/kg/day.
This article is part of a Special Issue titled "Cannabinoids and Epilepsy".
Growing clinical and pre-clinical evidence points to a critical role for cannabidiol (CBD), the largest phytochemical component of cannabis, as a potential pharmacotherapy for various neuropsychiatric disorders. In contrast to delta-9-tetrahydrocannabinol (THC), which is associated with acute and neurodevelopmental pro-psychotic side-effects, CBD possesses no known psychoactive or dependence-producing properties. However, evidence has demonstrated that CBD strongly modulates the mesolimbic dopamine (DA) system and may possess promising anti-psychotic properties. Despite the psychotropic differences between CBD and THC, little is known regarding their molecular and neuronal effects on the mesolimbic DA system, nor how these differential effects may relate to their potential pro vs. anti-psychotic properties. This review summarizes clinical and pre-clinical evidence demonstrating CBD’s modulatory effects on DA activity states within the mesolimbic pathway, functional interactions with the serotonin 5-HT1A receptor system, and their downstream molecular signaling effects. Together with clinical evidence showing that CBD may normalize affective and cognitive deficits associated with schizophrenia, CBD may represent a promising treatment for schizophrenia, acting through novel molecular and neuronal mesolimbic substrates.
There has been a dramatic surge in the interest of utilizing cannabis for epilepsy treatment in the US. Yet, access to cannabis for research and therapy is mired in conflicting regulatory policies and shifting public opinion. Understanding the current state of affairs in the medical cannabis debate requires an examination of the history of medical cannabis use. From ancient Chinese pharmacopeias to the current Phase III trials of pharmaceutical grade cannabidiol, this review covers the time span of cannabis use for epilepsy therapy so as to better assess the issues surrounding the modern medical opinion of cannabis use.
This article is part of a Special Issue titled Cannabinoids and Epilepsy.
Psoriasis is a chronic skin disease also affecting other sites such as joints. This disease highly depends on inflammation and angiogenesis as well as other pathways. At each step of the psoriasis molecular pathway, different inflammatory cytokines and angiogenic growth factors are involved such as hypoxia inducible factor-1 α (HIF-1 α), vascular endothelial growth factor (VEGF), matrix metalo proteinases (MMPs), basic fibroblast growth factor (bFGF), Angiopoitin-2, interleukin-8 (IL-8), IL-17, and IL-2. Beside the mentioned growth factors and cytokines, cellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) which play roles in both angiogenesis and inflammation are also involved in the pathogenesis. Cannabinoids are active compounds of Cannabina Sativa inducing their effects through cannabinoid receptors (CBs). JWH-133 is a synthetic cannabinoid with strong anti-angiogenic and anti-inflammatory activities. This agent is able to inhibit HIF-1 α, VEGF, MMPs, bFGF, IL-8, IL-17, and other mentioned cytokines and adhesion molecules both in vivo and in vitro. Altogether, authors suggest using this cannabinoid for treatment of psoriasis due to its potential in suppressing the two main steps of psoriatic pathogenesis. Of course complementary animal studies and human trials are still required.
UNLABELLED: Beta-myrcene, an acyclic unsubstituted monoterpene, and the essential oils which contain it are used as intermediates in the production of terpene alcohols (geraniol, nerol, and linalool), which, in turn, serve as intermediates in the production of aroma and flavor chemicals. Thus beta-myrcene is used widely in cosmetics, soaps, and detergents and as a flavoring additive in food and beverages. Beta-myrcene is also the major constituent of hop and bay oils, which are used in the manufacture of alcoholic beverages. Beta-myrcene was nominated for study by the National Institute of Environmental Health Sciences based on its high production volume, high level of human exposure, and structural relationship to d-limonene, which induced neoplasms in the kidneys of male rats in association with hyaline droplet nephropathy (NTP, 1990). Male and female F344/N rats and B6C3F1 mice were administered beta-myrcene (greater than 90% pure) by gavage for 3 months or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were administered 0, 0.25, 0.5, 1, 2, or 4 g beta-myrcene/kg body weight in corn oil by gavage, 5 days per week for 14 weeks. Additional groups of 10 male and 10 female special study rats were administered the same doses for 23 days. All core study rats in the 4 g/kg groups died during the first week of the study except one male that died on day 11. One to three rats in the 1 and 2 g/kg groups and one 0.5 g/kg male died by week 10 of the study. One 2 g/kg female died during the last week of the study. Except for lesion incidence data in groups administered 2 g/kg or less, data from rats that died early were excluded from the analysis and summary tables. Mean body weights were significantly decreased in male rats in the 0.5, 1, and 2 g/kg groups. Special study rats in the 4 g/kg groups died by the end of the first week. Dose-related clinical findings in animals that died early included thinness, lethargy, abnormal breathing, and ruffled fur. Right kidney and liver weights of dosed males and females were generally significantly greater than those of the vehicle controls. In special study rats evaluated on day 23, the incidences and severities of chronic progressive nephropathy (CPN) and renal tubule degeneration were increased in 2 g/kg males. At the end of the 3-month study, the incidences of renal tubule necrosis were significantly increased in all dosed groups of males and females. At 3 months, the incidences of olfactory epithelium degeneration in 2 g/kg males and females were significantly increased, and the severities were increased. The incidences of chronic inflammation in 1 and 2 g/kg males and females were significantly increased. All 2 g/kg males and females had splenic atrophy. In the mesenteric lymph node, significantly increased incidences of atrophy occurred in 2 g/kg males and 1 and 2 g/kg females. Acute inflammation of the forestomach occurred in four 2 g/kg females. The incidences of porphyrin pigmentation in the Harderian gland of males administered 0.5 g/kg or greater were significantly increased. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were administered 0, 0.25, 0.5, 1, 2, or 4 g beta-myrcene/kg body weight in corn oil by gavage, 5 days per week for 14 weeks. All 4 g/kg male and female mice died during week 1; nine 2 g/kg males and eight 2 g/kg females died by week 4. The mean body weights of 1 g/kg males were significantly less than those of the vehicle controls. Clinical findings in animals that did not survive to the end of the study included thinness, lethargy, and abnormal breathing. The right kidney weights of 1 g/kg females and the liver weights of females administered 0.5 or 1 g/kg were significantly increased. No histopathology changes were observed in mice administered 1 g/kg or less. The 2 and 4 g/kg mice were not evaluated due to early deaths. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were administered 0, 0.25, 0.5, or 1 g beta-myrcene/kg body weight in corn oil by gavage, 5 days per week for 105 weeks. All 1 g/kg male rats died before the end of the study due to renal toxicity. Compared to vehicle controls, the mean body weights of 0.25 and 0.5 g/kg males were slightly greater, and mean body weights of 1 g/kg males and females were at least 8% less than those of vehicle controls after 11 weeks and 13 weeks, respectively. In the standard evaluation of the kidney, the incidence of renal tubule adenoma was significantly increased in 0.5 g/kg male rats, and the combined incidences of renal tubule adenoma or carcinoma were significantly increased in 0.25 and 0.5 g/kg males. In both the extended evaluation and the combined standard and extended evaluations, the incidences of renal tubule adenoma and the combined incidences of renal tubule adenoma or carcinoma were significantly increased in the 0.25 and 0.5 g/kg groups of males. The incidences of renal tubule nephrosis (nephrosis) were markedly increased in all dosed groups of both sexes except in 0.25 g/kg females. The incidences of papillary mineralization in 0.25 and 0.5 g/kg males were significantly increased. Significantly increased incidences of nephropathy occurred in dosed females, and the severity was increased in the 0.5 and 1 g/kg males and females. The incidences of hyperplasia of the transitional epithelium lining the pelvis and overlying the renal papilla were significantly increased in all dosed groups of males and females. In male rats, the incidences of focal suppurative inflammation were significantly increased in the 0.25 and 0.5 g/kg groups. A significantly increased incidence of chronic active inflammation of the nose occurred in 0.5 g/kg males. Also in 0.5 g/kg males, the incidence of chronic active inflammation of the forestomach was increased. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were administered 0, 0.25, 0.5, or 1 g beta-myrcene/kg body weight in corn oil by gavage, 5 days per week for 104 or 105 weeks. Survival of 1 g/kg mice was significantly less than that of the vehicle controls; the cause of the deaths was uncertain. Mean body weights of 1 g/kg males were at least 8% less than those of the vehicle controls between week 8 and week 56. Mean body weights of 0.5 g/kg females were at least 7% less than those of the vehicle controls after week 17, and those of 1 g/kg females were at least 8% less from week 11 to week 96. The incidences of liver neoplasms were significantly increased in 0.25 and/or 0.5 g/kg males and 0.25 g/kg females. Liver neoplasms included hepatocellular adenoma and hepatocellular carcinoma in males and females and hepatoblastoma in males. The incidences of hepatocellular hypertrophy were significantly increased in 0.5 g/kg males and females, as was the incidence of mixed cell focus in 0.5 g/kg females. The incidences of bone marrow atrophy and lymph node follicle atrophy in the spleen were significantly increased in 0.5 g/kg females. In the forestomach, there were significantly increased incidences of inflammation and epithelial hyperplasia in 0.5 g/kg females.
This study was aimed to investigate whether treatment with purified cannabidiol (CBD) may counteract the development of experimental multiple sclerosis (MS), by targeting the PI3K/Akt/mTOR pathway. Although the PI3K/Akt/mTOR pathway was found to be activated by cannabinoids in several immune and non-immune cells, currently, there is no data about the effects of CBD in the PI3K/Akt/mTOR activity in MS. Experimental Autoimmune Encephalomyelitis (EAE), the most common model of MS, was induced in C57BL/6 mice by immunization with myelin oligodendroglial glycoprotein peptide (MOG)35-55. After EAE onset, which occurs approximately 14days after disease induction, mice were daily intraperitoneally treated with CBD (10mg/Kg mouse) and observed for clinical signs of EAE. At 28days from EAE-induction, mice were euthanized and spinal cord tissues were sampled to perform immunohistochemical evaluations and western blot analysis. Our results showed a clear downregulation of the PI3K/Akt/mTOR pathway following EAE induction. CBD treatment was able to restore it, increasing significantly the phosphorylation of PI3K, Akt and mTOR. Also, an increased level of BNDF in CBD-treated mice seems to be involved in the activation of PI3K/Akt/mTOR pathway. In addition, our data demonstrated that therapeutic efficacy of CBD treatment is due to reduction of pro-inflammatory cytokines, like IFN-γ and IL-17 together with an up-regulation of PPARγ. Finally, CBD was found to promote neuronal survival by inhibiting JNK and p38 MAP kinases. These results provide an interesting discovery about the regulation of the PI3K/Akt/mTOR pathway by cannabidiol administration, that could be a new potential therapeutic target for MS management.
Objective:
Tuberous sclerosis complex (TSC) is an autosomal-dominant genetic disorder with highly variable expression. The most common neurologic manifestation of TSC is epilepsy, which affects approximately 85% of patients, 63% of whom develop treatment-resistant epilepsy. Herein, we evaluate the efficacy, safety, and tolerability of cannabidiol (CBD), a nonpsychoactive compound derived from the marijuana plant, as an adjunct to current antiepileptic drugs in patients with refractory seizures in the setting of TSC.
Methods:
Eighteen of the 56 patients who have enrolled in our current expanded-access study of cannabidiol for patients with treatment-resistant epilepsy carry a diagnosis of TSC. After an initial baseline period of 1 month, patients began treatment with CBD. The initial dose of 5 mg/kg/day was increased by 5 mg/kg/day every week up to a maximum dose of 50 mg/kg/day, if tolerated. Weekly seizure frequencies, percent change in seizure frequencies, and responder rates were calculated during the 2nd, 3rd, 6th, 9th, and 12th month of treatment with CBD.
Results:
The median weekly seizure frequency during the baseline period was 22.0 (interquartile range [IQR] 14.8-57.4), which decreased to 13.3 (IQR 5.1-22.1) after 3 months of treatment with cannabidiol. The median percent change in total weekly seizure frequency was -48.8% (IQR -69.1% to -11.1%) after 3 months of treatment. The 50% responder rates over the course of the study were 50%, 50%, 38.9%, 50%, and 50% after 2, 3, 6, 9, and 12 months of treatment with CBD, respectively. In patients taking clobazam concurrently with CBD (n = 12), the responder rate after 3 months of treatment was 58.3%, compared to 33.3% in patients not taking clobazam (n = 6). Twelve (66.7%) of 18 patients in this study experienced at least one adverse event thought possibly related to CBD; the most common adverse events were drowsiness (n = 8, 44.4%), ataxia (n = 5, 27.8%), and diarrhea (n = 4, 22.2%).
Significance:
Although double-blind, placebo-controlled trials are still necessary, these findings suggest that cannabidiol may be an effective and well-tolerated treatment option for patients with refractory seizures in TSC.